CA1181404A - 4-or 5-oxoalkyl-3-phenyl-cycloalkan-1-one derivatives - Google Patents
4-or 5-oxoalkyl-3-phenyl-cycloalkan-1-one derivativesInfo
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- CA1181404A CA1181404A CA000444792A CA444792A CA1181404A CA 1181404 A CA1181404 A CA 1181404A CA 000444792 A CA000444792 A CA 000444792A CA 444792 A CA444792 A CA 444792A CA 1181404 A CA1181404 A CA 1181404A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
4- or 5-Oxoalkyl-3-phenylcycloalkan-l-one derivatives of the formula wherein R1 is H, alkanoyl, protecting group;
s is 1 or 2;
W is hydrogen, pyridyl or W1 wherein W1 is H, Cl or F;
Z is alkylene or O-interrupted alkylene;
Y' is -CH(R2")CH(R2)- or -CH(R3)CH2- wherein R2" is H or CH3, R2 and R3 are oxoalkyl, which are useful as analgesic agents and anti-emetic agents, also as inter-mediate for preparing corresponding cycloalkanol derivatives, are prepared by (a) oxidizing corresponding 4- or 5-alkenyl substituted derivatives, or (b) oxidizing corresponding 4- or 5-hydroxyalkyl substituted derivatives.
4- or 5-Oxoalkyl-3-phenylcycloalkan-l-one derivatives of the formula wherein R1 is H, alkanoyl, protecting group;
s is 1 or 2;
W is hydrogen, pyridyl or W1 wherein W1 is H, Cl or F;
Z is alkylene or O-interrupted alkylene;
Y' is -CH(R2")CH(R2)- or -CH(R3)CH2- wherein R2" is H or CH3, R2 and R3 are oxoalkyl, which are useful as analgesic agents and anti-emetic agents, also as inter-mediate for preparing corresponding cycloalkanol derivatives, are prepared by (a) oxidizing corresponding 4- or 5-alkenyl substituted derivatives, or (b) oxidizing corresponding 4- or 5-hydroxyalkyl substituted derivatives.
Description
This is a divisional application of Serial No. 386,091 filed September 17, 1981.
The parent application relates to novel3-[2-hydroxy-4-~substituted) phenyl]-4(or 5-~-(substituted)cycloalkanols use~ul as analgesic agents and as anti-emetic agents.
The present invention relates to novel 4- or 5-oxoalkyl-substituted -3-phenylcycloalkan-l-one derivatives useful as analgesic agents and anti-emetic agents and as intermediate ~or preparing cycloalkanol derivatives of the parent application.
Despite the current availability of a number of analgesic agents, the search for new and improved agents useful for the control o~ broad levels oE pain and accompanied by a minimum of side-effects continues. The most commonly used agent, aspir~n, is o~ no practical value for the control o~ severe pain and is known to exhibit various undesirable side-effects. Other analgesic agents, such as meperidine~ codeine, and morphine, possess addictive liability.
The need for improved and potent analgesic agents is, therefore, evident.
Compounds having utility as analgesics~ tranquilizers, sedatives, antianxièty agents and/or as anticonvulsants, diuretics and antidiarrheal agents are described in Belgian Pa~ents 870,404 and 870,~02, both granted March 12, 1979. Belgian Patent 870,404 describes 3-[2-hydroxy-4-(substituted) phenyl]cycloalkanones and cycloalkanols whichmay have at the 4-position o:~ the cycloalkanone or cycloalkanol residue, an alkyl, alkenyl, phenyl or phenylalkyl substituent; or, at the 5-position, an alkyl substituent, and Belgian Paten~
870,402 discloses certain 2-~acyclic substituted~phenols; namely, 2-(hydroxyalkyl) -4--(substituted)phenols and 2-(oxoalkyl)-4-(substituted)phenols.
United States Patent 3,576,887, issued April 27, 1971, discloses a series of l-(l'-hydroxy)alkyl-2-(o-hydroxyphenyl)cyclohexanes which exhibit , .
central nervous system depressant properties.
Our concurrently filed Canadian application, Serial No. 386,121, entitled "Pharmacologically Active ~-[2-Hydroxy-4-(Substituted)phenyl]Naphthalen
The parent application relates to novel3-[2-hydroxy-4-~substituted) phenyl]-4(or 5-~-(substituted)cycloalkanols use~ul as analgesic agents and as anti-emetic agents.
The present invention relates to novel 4- or 5-oxoalkyl-substituted -3-phenylcycloalkan-l-one derivatives useful as analgesic agents and anti-emetic agents and as intermediate ~or preparing cycloalkanol derivatives of the parent application.
Despite the current availability of a number of analgesic agents, the search for new and improved agents useful for the control o~ broad levels oE pain and accompanied by a minimum of side-effects continues. The most commonly used agent, aspir~n, is o~ no practical value for the control o~ severe pain and is known to exhibit various undesirable side-effects. Other analgesic agents, such as meperidine~ codeine, and morphine, possess addictive liability.
The need for improved and potent analgesic agents is, therefore, evident.
Compounds having utility as analgesics~ tranquilizers, sedatives, antianxièty agents and/or as anticonvulsants, diuretics and antidiarrheal agents are described in Belgian Pa~ents 870,404 and 870,~02, both granted March 12, 1979. Belgian Patent 870,404 describes 3-[2-hydroxy-4-(substituted) phenyl]cycloalkanones and cycloalkanols whichmay have at the 4-position o:~ the cycloalkanone or cycloalkanol residue, an alkyl, alkenyl, phenyl or phenylalkyl substituent; or, at the 5-position, an alkyl substituent, and Belgian Paten~
870,402 discloses certain 2-~acyclic substituted~phenols; namely, 2-(hydroxyalkyl) -4--(substituted)phenols and 2-(oxoalkyl)-4-(substituted)phenols.
United States Patent 3,576,887, issued April 27, 1971, discloses a series of l-(l'-hydroxy)alkyl-2-(o-hydroxyphenyl)cyclohexanes which exhibit , .
central nervous system depressant properties.
Our concurrently filed Canadian application, Serial No. 386,121, entitled "Pharmacologically Active ~-[2-Hydroxy-4-(Substituted)phenyl]Naphthalen
-2(1~1)-ones and 2-ols, Derivatives Thereof and Intermediates Therefore,"
describes a series of ~-[2-hydroxy-4-(substituted)-phenyl]naphthalen-2~lH)-ones and 2-ols useful as CNS agents and as antiemetic agents.
United States Patent 3,974,157 describes 2-phenylcyclohexanones which can be substituted in the phenyl ring with up ~otwo alkyl, hydroxy or alkoxy groups as intermediates for preparation of 1-(aminoalkyl)-2-phenylcyclohexanols useful as analgesics, local anesthetics and antiarrhythmics.
Chemical Abstracts 85, 176952f (1976) discloses a number of 3-phenyl-and 3-phenylalkylcyclohexanones as intermediates for 2-aminomethyl-3-phenyl ~or phenylalkyl)cyclohexanones which exhibit analgesic, sedative, antidepressant and anticonvulsant activities.
The present invention provides a process for making a compound having :Eormula ~II) O
~ ~ Z - W (II) wherein Rl ;s hydrogen, alkanoyl having from one to five carbon atoms, or a hydroxy-protecting group selected from the group consisting of a lower alkyl, tctrahydropyranyll benzyl and a substituted benzyl having as the substi-tuent alkyl having from one to four carbon atoms, halo or alkoxy having from one to four carbon atoms;
s is an integer of 1 or 2;
W is hydrogenJ pyridyl or ~ ~ Wl wherein Wl is hydrogen, chloro or fluoro, provided that when W is hydrogen, Z is (a) alkylene having from five to thirteen carbon atoms; or (b) -~alkl)m-0-(alk2)n-wherein each of (alkl) and (alk2) is alkylene having from one to thirteen carbon atoms; eachof m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alkl) plus (alk2) is not less than five or greater than ~hirteen; and at least one of m and n is l; or (c) -Z-W is 1,1-dimethyl-2-heptenyl;
when W is other than hydrogen, Z is ta) alkylene having from three to eight carbon atoms; or (b) -(alkl)m-0-(alk2)n- wherein each of (alkl) and (alk2) is alkylene having from one to eight carbon atoms; each of m andn is 0 or 1; with the provisos that the summation of carbon atoms in (alkl) plus (alk2) is not less thnn three or greater ~han eight; and at least one of m and n is l;
Y is -C}l(R2")CH(R2)- or -CH(R3)CH2- wherein R2" is hydrogen or methyl, R2 is a 4-position substituent and is oxoalkyl withup to six carbon atoms and R3 is a 5-position substituent and oxoalkyl with up to three carbon atoms;
which process comprises (A) oxidizing a compouncl of formula (II"), or l ketal thereof, ( ~ 2 ORl ~ ~ Z - W (II~) where:Ln s, Rl, Z and W are as defined above;and Y" is -CH(R2")CH(R2)- or ~CHtR3)C~12- wherein R2" is as defined above, R2 is a 4-position substituent and is alkenyl with up to six carbon atoms and R3 is a 5-position substituent and is alkenyl with up to three carbon atoms, or 4 a ~
(B) oxidizing a compound of formula (II"'~, or a ketal thereof, ~--T ORl Y" ~ l Z ~ W (II~
wherein s, Rl, Z and W are as defined above; and Y"' is -CH(R2")CH(R2 )- or -CH(R3)C~2- wherein R2" is as defined above, R is a 4-position substituent and is hydroxy-alkyl with up to six carbon atoms, and R3 is a 5-position substituent and is hydroxy-alkyl with up to three carbon atoms, (C) reacting a Grignard reagent derived from a compound of the formula ~r lORl' `~//\
Z - W
wherein Z and W are as defined above, Rl' is~hehydroxy protecting group defined aboveJ with 4-(acetal or ketal substituted alkyl)-2-cycloalken ~l-one of the formula o R
wherein R2" and s are as defined above~
R6 is acetal or ketal substi~uted alkyl, corresponding to the radical R2 defined above J
(D~ subjecting 4- or 5-oxoalkyl in a 4- or 5-oxoalkyl-3-phenyl-cycloalkan-l-one C-l ketal of the formula 7, ~
o - ~ o ~S --~ 1 ~ z - w wherein Z, W and s are as defined above, Rl' is the hydroxy protecting group defined above, V is -CH~R2")CH~)- or -CH~R5)CH2- wherein R2"is hydrogen or methyll R4 is a 4-position substituent and is oxoalkyl with less carbon a~oms than the desired radical R2 and R5 is a 5-position substituent and is oxoalkyl with less carbon atoms than the desired radical R3, to the Wittig reaction, followed by reduction of thus prepared 4- or S-~-oxoalkenyl compound, so as to prepare a compound of formula ~II) wherein R2 or R3 is ~-oxoalkyl, ~E~ reducing cyano group in a compound of the formula o OR
NC ~ ~
Z - W
wherein Rl, s, Z and W are as defined above, or a ketal thereo:E, to the formyl group, and (~) when required converting the ketal to the corresponding ketone and/or removing the hydro.xy protecting group, and/or acylating the hydroxy group.
The present invsntion also provides the compound of formula ~II) when prepared by the process me~tioned above.
o~
Also included in this invention as noted above are the pharmaceu-tically acceptable acid addition salts of those compounds of formula II which contain as the W variable pyridyl.
Representative of such pharmaceutically acceptable acid addi~ion salts are the mineral acid salts such asthe hydrochloride, hydrobromide, sul-fate, phosphate, nitrate; organic acid salts such as the citrate~ acetata, sulfosalicylate~ tartrate, glycolate,malate, malonate, maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, 2-hydroxy-3-naphthoate, lactate, mandelate and methanesulfonate.
Compounds of formula II wherein Rl is hydrogen exist, in solution, in equilibrium with their hemiketal forms. The keto and hemiketal forms of said compounds of formula II are included in this invention.
Compounds of formula II contain asymmetric centers at the 3-, the ~- or the 5-positions in the cycloalkyl moiety and may, of course, contain additional asymmetric centers in ~-Z-W) of the phenyl ring. Trans-relationship between the 3- and 4- substituents and the 3- and 5-substituents on the cyclo-alkyl moiety are avored because of the greater (quantitatively) biological activity.
For convenience, the above formula depicts the racemic cornpounds.
~0 However~ the above formula is considered to be generic to and embraclve oE the racemic modiEications of the compounds of this invention, the diastereomeric mixturcs, the pure enantiomers and diastereomers thereof. l'he utility of the racemic mixture, the diastereomeric mixture as well as of the pure enantiomers and diastereomers is determined by the biological evaluation procedures des--cribed below.
0 ~
Favored because of their greater biological activity relative to that of other compo~mds described herein are compoundsof formula wherein Rl is hydrogen, and Z and W have the values shown below:
Z m n W
_ _ . , . _ . _ . _ . .
C7_11 alkylene --- _ 11 C4 7 alkylene ~ Wl, pyridyl -~alkl)m-O-~alk2) - 0,1 1 ~ Wl, pyridyl each o~ ~alkl) and ~alk2) is Cl 7 alkylene wi-~hthe proviso that tho summation of carbon atoms in (alkl) plus (alk2) isnot less than four or 10 grea-ter than seven;
-~alkl)m-0-(alk2)n- 0,1 1 H
each of ~alkl) and (alk2) is Cl llalkylene with the proviso that the summation of carbon atoms in (alkl) plus (alk2) isnot less than seven or greater than eleven.
Preferred compounds of formula II are those favored compounds wherein:
each of R2" and Rl is hydrogen;
Z is C~CH3)2(CH2)6 and W is hydrogen, Z is C4 7 alkylene and W is phenyl;
Z is -O-alkylene having 7 to 9 carbon atoms and W is hyclrogen;
X is -0-alkylene having from 4 to 5 carbon atoms and W is phenyl.
The l-form of a given compound is preferred over the d-form thereof.
, , - 7 -The compounds of this invention having formula II wherein ~ is -CH(R ")CH(R2)- are prepared from the appropriate 2-bromo-5-(Z-W su~stituted~phenol by a series of reactions which comprises as the ~irst step protec~ion of the phenolic group. Suitable pro-tec~ing groups are those whic~ do not interfere with the subsequent reactions and which can be removed under condi~ions which do not cause undesired reactions at other sites of said compounds or of products produced therefrom. Representative of such protective gxoups are those phenolic protecting groups described by Raslam in Chapter 4 of "Protective Groups in Organic Chemistry," ~dited by J.F.W. McOmie~ Plenum Press~
London and New York (1973). Favored groups are methyl, ethyl, tetrahydropyranyl, benzyl or substituted benzyl wherein the substituent is, for example, alkyl having from one to ~our carbon atoms, halo (Clt Br~ F, I) and alkoxy having from one to four carbon atoms. The ether protecting, or blocking, groups can be removed through the use of hydrobromic acid in acetic acid or hydrobromic acid, 48% aqueous. The reaction is conducted ak elevated temperatures and desirably at the reflux temperatureO However, when Z is -(alkl)m-O-(alk2)~-, acids such as polyphosphoric acid or trifluoroacetic acid must be used to a~oid cleavage of the ether linkagea Other reagents such as hydriodic acid, pyridine hydro-chlorid~ or hydrobromide can be used to remove protecting ether groups such as methyl or ethyl groups. When the pro~ecting groups are benzyl or substituted benzyl groups, the~ can be removed by catalytic hydrogenolysis.
Suitable catalysts are palladium or platin~m, especially when sllpported on carbon. Alternatively, they can be removed by solvolysis using trifluoroacetic acid.
further procedure comprises trea~ent with n-but~
lithium in a reaction-inert solvent at room temperature.
_ g_ 8~404 The e~act chemical structure of the protecting group is not critical to this invention since its importance resides in its ability to perform in the manner described above. The selection and identifica-tion of appropriate protecting groups can easily andreadily be made by one skilled in the art. The suitability and effectivenes~s of a group as a hydroxy protecting group are determined by employing such a group in the herein-illustrated reaction sequences.
It should, -therefore, be a group which is easily removed to regenerate the hydroxy groups. Methyl, tet~a-hydropyranyl and benzyl are preferred protecting groups since they are readily removed.
The protected 2-bromo 5-(Z-W substituted)phenol is then reacted with magnesium in a reaction-inert solvent and generally in the presence o~ a promoter, e.g., cuprous salts such as the chloride, bromide a~d iodide (to promote 1,4-addition~ with the appropriate 4-R2'-2-cycloalken-l-one (eOg., 4-R2'-2-cyclohexen-1-one) wherein R~' is alkenyl or X'-substituted alkyl wherein X' is X or a precursor therefor, e.g., -Obenzyl as precursor for -OH; -CH(OCH3)2 or -HCOCH2CH2O as precursor for -CHO. Suitable reaction-inert solvents are cycLic and acyclic ethers such as, for example, tetrah~drofuran, dioxane and dimethyl ether of ethylene glycol (diglyme). The Grignard reagent is formed in ~nown manner, as, for example, by refluxing a mixture o one molar proportion of the bromo reactant and two molar proportions of magnesium in a reaction-inert solvent, e.g., tetrahydrof~ran. The resulting mixture is then cooled to a~out 0 C. to -20 C. The amount of cu~rous iodide used is not critical, but can var~f widely.
Molar proportions ranging from about 0.2 to about 0.02 moles per mole of bromo reactant af~ord satisfactor~f 3S yields of the cycloal~anone whe-ein the phe~olic hvdro~y group is protected (for~ula II" or II~I, Rl = a protecting group).
o ~
Alternatively, compounds of formulae II" and II"' are prepared by reaction of the copper derivative of an appropriate 3-(Z-W-substituted)phenol, the hydroxy group of which is suitably protected, with an appropriate 4- or 5-substituted cycloalk-2-en-1-one in a reaction-inert solvent at a low temperature, e.g., below -20C. Suitable protecting groups are those enumerated above except, of course~ benzyl or substituted benzyl which would be removed during preparation of theprecursor lithio derivative of the copper 3-(Z-W-substituted)phenol. An especially useful protecting group for this alterna~ive methodology is the tetrahydropyranyl group. Said protecting group is easily introduced into the phenol reactant, is stable to the conditions of subsequent reactions in which said protected compound serves as intermediate, and is conveniently removed by hydrolysis.
The copper derivative of the 3-(Z-W-substituted)-phenol is prepared from the lithio derivative of said phenol by trea~ment of said lithio derivative with l-hexyne copper. It undergoes 1~4-additionto the conjugated C=C-C=0 system of the cycloalk-2-en-1-one reactant, in contrast to the characteristic 1,2-addition of the corresponding lithio derivative.
This alternative 1,4-addition step, of course, gives rise to the same compounds as does the abovedescribed Grignard reaction. It generally ~0 affords better yields of the formulae II" and II"' compotmds.
It ~ill be noted that in a preparation of a cycloalkanol compound, the particular sequence exemplified (Examples 91-96) utilizes intermediates wherein the Z-W group is 1,1-dimethyl-2-heptenyl and which is hydrogenated in the last step of the sequence to l,l-dimethylheptyl. Reduction of said 1,1-dimethyl-2-heptenyl group can, of course, be accomplished at any stage of the sequence if desired, i.e., it need not be delayed until the final step.
4 0 ~
The protected cycloalkanone is then treated with an appropriate reagent to remove the protec~ing group, if desired. The benzyl group is conveniently removed by the method described above. If the protecting group is an alkyl group (methyl or ethyl), it is removed by the above-mentioned methods or by treatment with, for example, pyridine hydrochloride. The tetrahydropyranyl group is removed by means of an acidic reagent.
When the appropriate ~-R2'-2-cycloalken-1-one (wherein R2' is R2 or R2) is not available or is not readily obtainable by kno~m me~hods, compounds of formula II"' wherein R2 is oxo-substituted (Cl 6)alkyl, and especially those wherein R2 is formyl, serve as intermediates for all other formula II
compounds.
When R2' is an alkenyl group, the cycloalkanones (formula II") thus produced serve as intermediates for preparation of the desired cycloalkanones wherein R2 is oxo-substituted alkyl as defined above.
The cycloalkanol compounds, which isthe subject matter of the parent application, may be prepared from the protected cycloalkanones ot` ~ormula II, II" or II"' by reduction. Sodium borohydride is favored as reducing agent in this step.
Compounds oE formula (II") having alXenyl as R2 or R3 may be transEormed to corresponding hydroxyalkyl derivatives via hydroboration-oxidation sing borane in tetrahydrofuran or diethyleneglycol dimethyl ether (diglyme~
at 0 to 50C. The intermediate borane produc~ is not isolated but is directly oxidized with alkaline hydrogen peroxide to the alcohol. The alcohols thus produced correspond to anti-~larkovnikov addition o~ the elements of water to the double bond.
Further, hydroxyalkyl derivatives can also beproduced by oxymercura-~ ~8~0~
tion-demercuration using mercuric acetate in water followed by reduction (sodium borohydride) of the intermediate hydroxy mercurial derivative. The reaction is carried out at ambient temperature using an aqueous mercuric acetate/tetrahydrofuran medium. The in~ermediate is not separated,but is reduced in situ to the alcohol. Addi~ion occurs opposite to that of the hydroboration-oxidation reaction; namely, Markovnikov addition, the elements of water being added to the double bond in a manner opposite to that of the hydroboration-oxidation reaction to produce secondary alcohols.
The alcohols serve as intermediates for production of corresponding 1() aldehydes and ketones (oxoalkyl compounds) by oxidation with a suitable oxidi-zing agent such as pyridinium chlorochromate. The resulting oxo compounds in turn serve as intermediates for increasing the chain length of the alkyl groups having said oxo functionality and, of coursel for introducing branching into said alkyl group. The Wittig reaction, using the appropriate ylide, serves admirably for this purpose. For example, reaction of an oxoalkyl group with triphenylphosphonium methylide converts the oxo group to a methylene (= CH2) group. Ilydroboration-oxidation, ai`fords a primary or secondary alcohol, it-self a useful intermediate.
Formula II compounds wherein R2 or R3 is oxo substituted allcyl are conveniently prepared by oxidation of corresponding compounds oE formula (Il") whereln R2 or R3 is an alkenyl group having one more carbon atom than R2 or R3. Sodium metaperiodate and a catalytic amount oE osmium tetroxide in aqueous tetrahydrofuran or dioxane at ambient temperature is Eavored as oxidizing agent sillce it tends to minimize oxidation beyond the aldehyde stage. However, despite its relative mildness as an oxidant compared to, for example, sodium metaperiodate/potassium permanganate, some oxidation to the corresponding acid and the corresponding hydroxy ketone does occur.
q. ~
They can also be prepared by Grignard reaction of the appropriate ~-(acetal or ketal substituted alkyl)-2-cycloalken-l-one with the appropriate 2-bromo-5-(Z-W substituted)phenol according to the procedure de~cribed above.
The acetal or ketal group is then transformed by treatment with acid, e.g., a mineral acid such as HCl, to the oxo group.
A favored procedure for preparation of compounds of fGrmula II wherein Z-W is -O-~alk2) -W comprises selective alkylation of the appropriate 3-(2,4-dihydroxyphenyl)-4-(R2'-substituted)-cycloalkan-l-one in a reaction-iner~
solvent according to the procedure described below. The 3-(2,4-dibenzyloxy-1() phenyl)-4-~R2~-substituted)-cycloalkanone is, if no transformations are to be carried out on the R2'-group, debenzylated via hydrogen over palladium-on-charcoal to the corresponding 3-(2,4-dihydroxy}4-(R2'-substituted)cycloalkane and then converted to a ketal.
Ketal formation is accomplished according to well-known procedures for ketalization, such as reaction of said 3-~2,4-dihydroxyphenyl)cycloalkanone with an alcohol, especially an alcohol having from one to four carbon atoms, in the presence of an acid, such as sulfuric acid, p-toluenesulfonic acid, hydrogen chloride, under conditions which remove the by-product water. A favored procedure comprises reaction of said 3-~2,4-dihydroxyphenyl)cycloalkanone with an orthoformic ester in solution in an alcohol corresponding to the alcohol moiety of the orthoformic ester. Trimethyl orthoformate and methanol are favored reactants along with concentrated sulfuric acid, anhydrous hydrogen chloride, or ammonium chloride as catalyst.
The ketal thus produced is then alkylated by reaction with an approp-riate alkylating agent such as W-Z-X" wherein W and Z are as defined above, and X" is selected from the group consisting of chloro, bromo, mesyloxy (CH3-SO2-O) -t ~
and tosyloxy ~p-CH3-C6H4-S02-0) in the presence of an acid acceptor, e.g., sodiumor potassium carbonate. The alkylated ketal is then d0ketalized by treatment with aqueous acid accordillg to known procedures.
The 3-[2-hydroxy-4-(-0-(alk2)n-W-substituted)phenyl]-4-(R2'-substituted)cycloalkanones thus produced are converted to corresponding 4-oxoalkyl derivatives by procedures described above.
When transformations are to be conducted on group R2' as precursor ~o group R2, e.g., alkenyl to oxoalkyl; -CH~OCH3)2 to -CHO; the desired transformations are carried out prior to removal of the protective, i.e., benzyl groups. For example, when R2' is alkenyl, said group is oxidized described above, either by direct conversion from the 3-~2,4-dibenzyloxyphenyl)-4-(2-propenyL)cycloalkanone, or by first converting the ~cetone to a 'cetal, followed ~y oxidation of the pxopen~l group and then deketalizakion.
Formula II compounds wherein R2 is oxo sub-stituted alkyl serve as intermediates for preparation of oxo substitute~ alkyl derivatives having increased chain len~th via the Wittig reaction. A xepresentative proceduxe comprises, for example, reacting an appropri ate 2 (1,3-dio~olan-2-yl)alkyl triphenylphosphonium bromide at about 10C. to about 80C. with sodium dimsylate in dimethyl sulfoxide to generate the corxespond.ing ylide in situ. To the thus produced ylide is then added an appropriate reactant such as 3 lS (2-benzylox~-4-(Z-W substituted)phenyl-4-(2-oxoethyl)-cycloalXanone ethylene ketal in a suita~le solvent ~uch as dimethyl sulfoxide at a temperature of from about 10C. to about 80C. The product, a 3-(2-benzyloxy-4-(Z-W substituted)phenyl)-4-(~-oxoalk-2-enyl)cycloalkanone bis ethylene ketal, is recovered by known methods such as extraction and column chroma-tography on silica gel. In this Wittig ~eactio~, the oxo group of the cycloalkanone moiety is protected by conversion to a ketal. If desired, th~ product is subjected to acid hydrolysis to regenerate the oxo groups. However~ when the product is to be subjected t~ furthex reactions, it is advantageous to retain the bis eth~lene }cetal protecting groups on the product.
Reduction of the protec~ed t~-oxoalkenyl) group of ~he thus produced compounds using catalytic hydrogenation over a noble metal catalyst, e.g., Pd/C, affords the corres?onding protected (~-oxoalkyl) com-pound. TreatmPnt of the reduced p-oduct with aqueous acid (HCl) as described herein provides the ~-oxoalkyl derivative of formula II wherein R2 is ~-oxoalkyl. Sodium borohydride reduction of the protected compound affords a corresponding hydroxyalkyl compound wherein R2 is ~-hydroxyalkyl.
Formation of a secondary alcohol group is readily achieved by Grignard reaction on an appropriate compound of formula II, the l-oxo group of which is protected as an alkylene ketal, and in which R2 is oxoal]cyl.
Compounds of formula II wherein Y is -CHtR3)CH2- are prepared via the previously described Grignard reaction from the appropriate 5-[2-benzyloxy-~-(Z-W substituted)phenyl]-2-cycloalken-1-ones, the p~eparation of which are described in Belgian Patent 870,404, published March 12, 1979. Nucleophilic addition of the elements of HCN to said 2-cycloalken-l-one compounds by reaction thereof with aqueous sodium or potassium cyanide affords the corres-ponding trans-3-[2-benzyloxy-4-(Z-W substituted)phenyl]-5-cyano cycloalkanones which are valuable intermediates. Reduction of the oxo group of the cyclo-alkanone moiety by means of sodium borohydride yields the corresponding trans-cis hydroxy compound. It is converted to the corresponding trans-trans compound by refluxing in t-butanol solu~ion in the presence of potassium t-butoxide.
The stereoisomeric cis-3[2-benzyloxy-4-(Z-W substituted)phenyl]-cis 5-cyanocycloalkanols are prepared by oxidation of the trans-trans steroisomers using, for example, Jones' reagent followed by sodium borohydride reduction of the thus-produced cis-3-[2-benzyloxy-4-(Z-W substituted)phenyl]-5-cyanocyclo-alkanone.
Each of the above-mentioned 5-cyanocycloalkanol and cycloalkanone derivatives is also a valuable intermediate. The cyano group is readily con-verted by reduction with diisobutyl aluminum hydride (DIBAL-H) to the corres-ponding formyl derivative. The procedure comprises reacting the cyano derivative - 16 -with DIBAL-H, two equivalents, in toluene at a low temperature, e.g., 0 C.
to -65C., followed by treating the reaction with dilute acid, e.g., a mineral acid such as sulfuric acid. The formyl derivative is recovered by standard procedures such as extraction with ether and evaporation of the solvent.
Reduction of the formyl derivative, e.g., by sodium borohydride, affords the corresponding hydroxymethyl derivative. In the above reactionsthe benzyl ether derivative of the 3-(2-hydroxy-~-(Z-W substituted)phenyl)-5-cyanocycloalkanone is used as reactant in order ~o avoid reactions at the phenolic hydroxy group.
The protecting benzyl group is removed by methods described above.
The 5-formyl derivative serves as intermediates for preparing oxo substltuted alkyl derivatives having increased chain length via the Wittig reaction,as described above as regards R2.
Acyl derivatives of formula II compounds wherein Rl is hydrogen, are prepared by acylation with the appropriate alkanoic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide~ or by reac-tion with the appropriate alkanoic acid chloride or anhydride in the presence of a base such as pyridine.
The analgesic properties of the compounds of the parent application are determined by tests using nociceptive stimuli. It isnoted that compounds 2n of formula II wherein Rl is a hydroxy protecting group are not pharmacologically active for the purposes described herein but are useful as intermediates :Eor said compounds wherein Rl is hydrogen.
~ \
Tésts Using Thermal Nocice~tive Stimuli a) Mouse Hot Plate Analgesic Testing The method used is modified after Woolfe and MacDonald, J. Pharmacol. ~. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied to the feet of mice on a l/8-inch thick aluminum p]ate. A
250 watt reflector infrared heat lamp is placed under the bottom of the aluminum plate. A thermal regulator, connected to thermistors on the plate surface, programs the heat lamp to maintain a cons~ant temperature of 57C. Each mouse is dropped into a glass cylinder (6 1/2-inch diameter) resting on the hot plate, and _ 19_ ming is begun when the animal's fePt touch the plate. The mouse is observed at 0.5 and 2 hours after treatment with the test compound for the first "~licking"
movemen~s of one or both hind feet, or until 10 seconds elapse w.ithout such movementsO Morphine has an MP~50 =
~-5.6 mg./kg. (sOc.).
b) Mouse Tail ~ ng Tail flick testing in mice is modified after DtAmour and Smith, J. Phaxmacol. Exp. Ther., 72, 74~79 (1941) using controlle.d high inten~ity heat applied to the ~ail. Each mouse is placed in a snug-fit~ing metal cylinder, with the tail protruding through one end. This cylinde.r is arranged so that ~he tail lies flat over a concealed heat lamp. At the onset of testing, an aluminum flag over the lamp is drawn back, allowing the light beam to pass through the slit and focus o~to the end of ~he tail. A timer is simultaneously activated. The latency of a sudden flick of the tail is a~cer~ained~ Untreated mice usually react within
describes a series of ~-[2-hydroxy-4-(substituted)-phenyl]naphthalen-2~lH)-ones and 2-ols useful as CNS agents and as antiemetic agents.
United States Patent 3,974,157 describes 2-phenylcyclohexanones which can be substituted in the phenyl ring with up ~otwo alkyl, hydroxy or alkoxy groups as intermediates for preparation of 1-(aminoalkyl)-2-phenylcyclohexanols useful as analgesics, local anesthetics and antiarrhythmics.
Chemical Abstracts 85, 176952f (1976) discloses a number of 3-phenyl-and 3-phenylalkylcyclohexanones as intermediates for 2-aminomethyl-3-phenyl ~or phenylalkyl)cyclohexanones which exhibit analgesic, sedative, antidepressant and anticonvulsant activities.
The present invention provides a process for making a compound having :Eormula ~II) O
~ ~ Z - W (II) wherein Rl ;s hydrogen, alkanoyl having from one to five carbon atoms, or a hydroxy-protecting group selected from the group consisting of a lower alkyl, tctrahydropyranyll benzyl and a substituted benzyl having as the substi-tuent alkyl having from one to four carbon atoms, halo or alkoxy having from one to four carbon atoms;
s is an integer of 1 or 2;
W is hydrogenJ pyridyl or ~ ~ Wl wherein Wl is hydrogen, chloro or fluoro, provided that when W is hydrogen, Z is (a) alkylene having from five to thirteen carbon atoms; or (b) -~alkl)m-0-(alk2)n-wherein each of (alkl) and (alk2) is alkylene having from one to thirteen carbon atoms; eachof m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alkl) plus (alk2) is not less than five or greater than ~hirteen; and at least one of m and n is l; or (c) -Z-W is 1,1-dimethyl-2-heptenyl;
when W is other than hydrogen, Z is ta) alkylene having from three to eight carbon atoms; or (b) -(alkl)m-0-(alk2)n- wherein each of (alkl) and (alk2) is alkylene having from one to eight carbon atoms; each of m andn is 0 or 1; with the provisos that the summation of carbon atoms in (alkl) plus (alk2) is not less thnn three or greater ~han eight; and at least one of m and n is l;
Y is -C}l(R2")CH(R2)- or -CH(R3)CH2- wherein R2" is hydrogen or methyl, R2 is a 4-position substituent and is oxoalkyl withup to six carbon atoms and R3 is a 5-position substituent and oxoalkyl with up to three carbon atoms;
which process comprises (A) oxidizing a compouncl of formula (II"), or l ketal thereof, ( ~ 2 ORl ~ ~ Z - W (II~) where:Ln s, Rl, Z and W are as defined above;and Y" is -CH(R2")CH(R2)- or ~CHtR3)C~12- wherein R2" is as defined above, R2 is a 4-position substituent and is alkenyl with up to six carbon atoms and R3 is a 5-position substituent and is alkenyl with up to three carbon atoms, or 4 a ~
(B) oxidizing a compound of formula (II"'~, or a ketal thereof, ~--T ORl Y" ~ l Z ~ W (II~
wherein s, Rl, Z and W are as defined above; and Y"' is -CH(R2")CH(R2 )- or -CH(R3)C~2- wherein R2" is as defined above, R is a 4-position substituent and is hydroxy-alkyl with up to six carbon atoms, and R3 is a 5-position substituent and is hydroxy-alkyl with up to three carbon atoms, (C) reacting a Grignard reagent derived from a compound of the formula ~r lORl' `~//\
Z - W
wherein Z and W are as defined above, Rl' is~hehydroxy protecting group defined aboveJ with 4-(acetal or ketal substituted alkyl)-2-cycloalken ~l-one of the formula o R
wherein R2" and s are as defined above~
R6 is acetal or ketal substi~uted alkyl, corresponding to the radical R2 defined above J
(D~ subjecting 4- or 5-oxoalkyl in a 4- or 5-oxoalkyl-3-phenyl-cycloalkan-l-one C-l ketal of the formula 7, ~
o - ~ o ~S --~ 1 ~ z - w wherein Z, W and s are as defined above, Rl' is the hydroxy protecting group defined above, V is -CH~R2")CH~)- or -CH~R5)CH2- wherein R2"is hydrogen or methyll R4 is a 4-position substituent and is oxoalkyl with less carbon a~oms than the desired radical R2 and R5 is a 5-position substituent and is oxoalkyl with less carbon atoms than the desired radical R3, to the Wittig reaction, followed by reduction of thus prepared 4- or S-~-oxoalkenyl compound, so as to prepare a compound of formula ~II) wherein R2 or R3 is ~-oxoalkyl, ~E~ reducing cyano group in a compound of the formula o OR
NC ~ ~
Z - W
wherein Rl, s, Z and W are as defined above, or a ketal thereo:E, to the formyl group, and (~) when required converting the ketal to the corresponding ketone and/or removing the hydro.xy protecting group, and/or acylating the hydroxy group.
The present invsntion also provides the compound of formula ~II) when prepared by the process me~tioned above.
o~
Also included in this invention as noted above are the pharmaceu-tically acceptable acid addition salts of those compounds of formula II which contain as the W variable pyridyl.
Representative of such pharmaceutically acceptable acid addi~ion salts are the mineral acid salts such asthe hydrochloride, hydrobromide, sul-fate, phosphate, nitrate; organic acid salts such as the citrate~ acetata, sulfosalicylate~ tartrate, glycolate,malate, malonate, maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, 2-hydroxy-3-naphthoate, lactate, mandelate and methanesulfonate.
Compounds of formula II wherein Rl is hydrogen exist, in solution, in equilibrium with their hemiketal forms. The keto and hemiketal forms of said compounds of formula II are included in this invention.
Compounds of formula II contain asymmetric centers at the 3-, the ~- or the 5-positions in the cycloalkyl moiety and may, of course, contain additional asymmetric centers in ~-Z-W) of the phenyl ring. Trans-relationship between the 3- and 4- substituents and the 3- and 5-substituents on the cyclo-alkyl moiety are avored because of the greater (quantitatively) biological activity.
For convenience, the above formula depicts the racemic cornpounds.
~0 However~ the above formula is considered to be generic to and embraclve oE the racemic modiEications of the compounds of this invention, the diastereomeric mixturcs, the pure enantiomers and diastereomers thereof. l'he utility of the racemic mixture, the diastereomeric mixture as well as of the pure enantiomers and diastereomers is determined by the biological evaluation procedures des--cribed below.
0 ~
Favored because of their greater biological activity relative to that of other compo~mds described herein are compoundsof formula wherein Rl is hydrogen, and Z and W have the values shown below:
Z m n W
_ _ . , . _ . _ . _ . .
C7_11 alkylene --- _ 11 C4 7 alkylene ~ Wl, pyridyl -~alkl)m-O-~alk2) - 0,1 1 ~ Wl, pyridyl each o~ ~alkl) and ~alk2) is Cl 7 alkylene wi-~hthe proviso that tho summation of carbon atoms in (alkl) plus (alk2) isnot less than four or 10 grea-ter than seven;
-~alkl)m-0-(alk2)n- 0,1 1 H
each of ~alkl) and (alk2) is Cl llalkylene with the proviso that the summation of carbon atoms in (alkl) plus (alk2) isnot less than seven or greater than eleven.
Preferred compounds of formula II are those favored compounds wherein:
each of R2" and Rl is hydrogen;
Z is C~CH3)2(CH2)6 and W is hydrogen, Z is C4 7 alkylene and W is phenyl;
Z is -O-alkylene having 7 to 9 carbon atoms and W is hyclrogen;
X is -0-alkylene having from 4 to 5 carbon atoms and W is phenyl.
The l-form of a given compound is preferred over the d-form thereof.
, , - 7 -The compounds of this invention having formula II wherein ~ is -CH(R ")CH(R2)- are prepared from the appropriate 2-bromo-5-(Z-W su~stituted~phenol by a series of reactions which comprises as the ~irst step protec~ion of the phenolic group. Suitable pro-tec~ing groups are those whic~ do not interfere with the subsequent reactions and which can be removed under condi~ions which do not cause undesired reactions at other sites of said compounds or of products produced therefrom. Representative of such protective gxoups are those phenolic protecting groups described by Raslam in Chapter 4 of "Protective Groups in Organic Chemistry," ~dited by J.F.W. McOmie~ Plenum Press~
London and New York (1973). Favored groups are methyl, ethyl, tetrahydropyranyl, benzyl or substituted benzyl wherein the substituent is, for example, alkyl having from one to ~our carbon atoms, halo (Clt Br~ F, I) and alkoxy having from one to four carbon atoms. The ether protecting, or blocking, groups can be removed through the use of hydrobromic acid in acetic acid or hydrobromic acid, 48% aqueous. The reaction is conducted ak elevated temperatures and desirably at the reflux temperatureO However, when Z is -(alkl)m-O-(alk2)~-, acids such as polyphosphoric acid or trifluoroacetic acid must be used to a~oid cleavage of the ether linkagea Other reagents such as hydriodic acid, pyridine hydro-chlorid~ or hydrobromide can be used to remove protecting ether groups such as methyl or ethyl groups. When the pro~ecting groups are benzyl or substituted benzyl groups, the~ can be removed by catalytic hydrogenolysis.
Suitable catalysts are palladium or platin~m, especially when sllpported on carbon. Alternatively, they can be removed by solvolysis using trifluoroacetic acid.
further procedure comprises trea~ent with n-but~
lithium in a reaction-inert solvent at room temperature.
_ g_ 8~404 The e~act chemical structure of the protecting group is not critical to this invention since its importance resides in its ability to perform in the manner described above. The selection and identifica-tion of appropriate protecting groups can easily andreadily be made by one skilled in the art. The suitability and effectivenes~s of a group as a hydroxy protecting group are determined by employing such a group in the herein-illustrated reaction sequences.
It should, -therefore, be a group which is easily removed to regenerate the hydroxy groups. Methyl, tet~a-hydropyranyl and benzyl are preferred protecting groups since they are readily removed.
The protected 2-bromo 5-(Z-W substituted)phenol is then reacted with magnesium in a reaction-inert solvent and generally in the presence o~ a promoter, e.g., cuprous salts such as the chloride, bromide a~d iodide (to promote 1,4-addition~ with the appropriate 4-R2'-2-cycloalken-l-one (eOg., 4-R2'-2-cyclohexen-1-one) wherein R~' is alkenyl or X'-substituted alkyl wherein X' is X or a precursor therefor, e.g., -Obenzyl as precursor for -OH; -CH(OCH3)2 or -HCOCH2CH2O as precursor for -CHO. Suitable reaction-inert solvents are cycLic and acyclic ethers such as, for example, tetrah~drofuran, dioxane and dimethyl ether of ethylene glycol (diglyme). The Grignard reagent is formed in ~nown manner, as, for example, by refluxing a mixture o one molar proportion of the bromo reactant and two molar proportions of magnesium in a reaction-inert solvent, e.g., tetrahydrof~ran. The resulting mixture is then cooled to a~out 0 C. to -20 C. The amount of cu~rous iodide used is not critical, but can var~f widely.
Molar proportions ranging from about 0.2 to about 0.02 moles per mole of bromo reactant af~ord satisfactor~f 3S yields of the cycloal~anone whe-ein the phe~olic hvdro~y group is protected (for~ula II" or II~I, Rl = a protecting group).
o ~
Alternatively, compounds of formulae II" and II"' are prepared by reaction of the copper derivative of an appropriate 3-(Z-W-substituted)phenol, the hydroxy group of which is suitably protected, with an appropriate 4- or 5-substituted cycloalk-2-en-1-one in a reaction-inert solvent at a low temperature, e.g., below -20C. Suitable protecting groups are those enumerated above except, of course~ benzyl or substituted benzyl which would be removed during preparation of theprecursor lithio derivative of the copper 3-(Z-W-substituted)phenol. An especially useful protecting group for this alterna~ive methodology is the tetrahydropyranyl group. Said protecting group is easily introduced into the phenol reactant, is stable to the conditions of subsequent reactions in which said protected compound serves as intermediate, and is conveniently removed by hydrolysis.
The copper derivative of the 3-(Z-W-substituted)-phenol is prepared from the lithio derivative of said phenol by trea~ment of said lithio derivative with l-hexyne copper. It undergoes 1~4-additionto the conjugated C=C-C=0 system of the cycloalk-2-en-1-one reactant, in contrast to the characteristic 1,2-addition of the corresponding lithio derivative.
This alternative 1,4-addition step, of course, gives rise to the same compounds as does the abovedescribed Grignard reaction. It generally ~0 affords better yields of the formulae II" and II"' compotmds.
It ~ill be noted that in a preparation of a cycloalkanol compound, the particular sequence exemplified (Examples 91-96) utilizes intermediates wherein the Z-W group is 1,1-dimethyl-2-heptenyl and which is hydrogenated in the last step of the sequence to l,l-dimethylheptyl. Reduction of said 1,1-dimethyl-2-heptenyl group can, of course, be accomplished at any stage of the sequence if desired, i.e., it need not be delayed until the final step.
4 0 ~
The protected cycloalkanone is then treated with an appropriate reagent to remove the protec~ing group, if desired. The benzyl group is conveniently removed by the method described above. If the protecting group is an alkyl group (methyl or ethyl), it is removed by the above-mentioned methods or by treatment with, for example, pyridine hydrochloride. The tetrahydropyranyl group is removed by means of an acidic reagent.
When the appropriate ~-R2'-2-cycloalken-1-one (wherein R2' is R2 or R2) is not available or is not readily obtainable by kno~m me~hods, compounds of formula II"' wherein R2 is oxo-substituted (Cl 6)alkyl, and especially those wherein R2 is formyl, serve as intermediates for all other formula II
compounds.
When R2' is an alkenyl group, the cycloalkanones (formula II") thus produced serve as intermediates for preparation of the desired cycloalkanones wherein R2 is oxo-substituted alkyl as defined above.
The cycloalkanol compounds, which isthe subject matter of the parent application, may be prepared from the protected cycloalkanones ot` ~ormula II, II" or II"' by reduction. Sodium borohydride is favored as reducing agent in this step.
Compounds oE formula (II") having alXenyl as R2 or R3 may be transEormed to corresponding hydroxyalkyl derivatives via hydroboration-oxidation sing borane in tetrahydrofuran or diethyleneglycol dimethyl ether (diglyme~
at 0 to 50C. The intermediate borane produc~ is not isolated but is directly oxidized with alkaline hydrogen peroxide to the alcohol. The alcohols thus produced correspond to anti-~larkovnikov addition o~ the elements of water to the double bond.
Further, hydroxyalkyl derivatives can also beproduced by oxymercura-~ ~8~0~
tion-demercuration using mercuric acetate in water followed by reduction (sodium borohydride) of the intermediate hydroxy mercurial derivative. The reaction is carried out at ambient temperature using an aqueous mercuric acetate/tetrahydrofuran medium. The in~ermediate is not separated,but is reduced in situ to the alcohol. Addi~ion occurs opposite to that of the hydroboration-oxidation reaction; namely, Markovnikov addition, the elements of water being added to the double bond in a manner opposite to that of the hydroboration-oxidation reaction to produce secondary alcohols.
The alcohols serve as intermediates for production of corresponding 1() aldehydes and ketones (oxoalkyl compounds) by oxidation with a suitable oxidi-zing agent such as pyridinium chlorochromate. The resulting oxo compounds in turn serve as intermediates for increasing the chain length of the alkyl groups having said oxo functionality and, of coursel for introducing branching into said alkyl group. The Wittig reaction, using the appropriate ylide, serves admirably for this purpose. For example, reaction of an oxoalkyl group with triphenylphosphonium methylide converts the oxo group to a methylene (= CH2) group. Ilydroboration-oxidation, ai`fords a primary or secondary alcohol, it-self a useful intermediate.
Formula II compounds wherein R2 or R3 is oxo substituted allcyl are conveniently prepared by oxidation of corresponding compounds oE formula (Il") whereln R2 or R3 is an alkenyl group having one more carbon atom than R2 or R3. Sodium metaperiodate and a catalytic amount oE osmium tetroxide in aqueous tetrahydrofuran or dioxane at ambient temperature is Eavored as oxidizing agent sillce it tends to minimize oxidation beyond the aldehyde stage. However, despite its relative mildness as an oxidant compared to, for example, sodium metaperiodate/potassium permanganate, some oxidation to the corresponding acid and the corresponding hydroxy ketone does occur.
q. ~
They can also be prepared by Grignard reaction of the appropriate ~-(acetal or ketal substituted alkyl)-2-cycloalken-l-one with the appropriate 2-bromo-5-(Z-W substituted)phenol according to the procedure de~cribed above.
The acetal or ketal group is then transformed by treatment with acid, e.g., a mineral acid such as HCl, to the oxo group.
A favored procedure for preparation of compounds of fGrmula II wherein Z-W is -O-~alk2) -W comprises selective alkylation of the appropriate 3-(2,4-dihydroxyphenyl)-4-(R2'-substituted)-cycloalkan-l-one in a reaction-iner~
solvent according to the procedure described below. The 3-(2,4-dibenzyloxy-1() phenyl)-4-~R2~-substituted)-cycloalkanone is, if no transformations are to be carried out on the R2'-group, debenzylated via hydrogen over palladium-on-charcoal to the corresponding 3-(2,4-dihydroxy}4-(R2'-substituted)cycloalkane and then converted to a ketal.
Ketal formation is accomplished according to well-known procedures for ketalization, such as reaction of said 3-~2,4-dihydroxyphenyl)cycloalkanone with an alcohol, especially an alcohol having from one to four carbon atoms, in the presence of an acid, such as sulfuric acid, p-toluenesulfonic acid, hydrogen chloride, under conditions which remove the by-product water. A favored procedure comprises reaction of said 3-~2,4-dihydroxyphenyl)cycloalkanone with an orthoformic ester in solution in an alcohol corresponding to the alcohol moiety of the orthoformic ester. Trimethyl orthoformate and methanol are favored reactants along with concentrated sulfuric acid, anhydrous hydrogen chloride, or ammonium chloride as catalyst.
The ketal thus produced is then alkylated by reaction with an approp-riate alkylating agent such as W-Z-X" wherein W and Z are as defined above, and X" is selected from the group consisting of chloro, bromo, mesyloxy (CH3-SO2-O) -t ~
and tosyloxy ~p-CH3-C6H4-S02-0) in the presence of an acid acceptor, e.g., sodiumor potassium carbonate. The alkylated ketal is then d0ketalized by treatment with aqueous acid accordillg to known procedures.
The 3-[2-hydroxy-4-(-0-(alk2)n-W-substituted)phenyl]-4-(R2'-substituted)cycloalkanones thus produced are converted to corresponding 4-oxoalkyl derivatives by procedures described above.
When transformations are to be conducted on group R2' as precursor ~o group R2, e.g., alkenyl to oxoalkyl; -CH~OCH3)2 to -CHO; the desired transformations are carried out prior to removal of the protective, i.e., benzyl groups. For example, when R2' is alkenyl, said group is oxidized described above, either by direct conversion from the 3-~2,4-dibenzyloxyphenyl)-4-(2-propenyL)cycloalkanone, or by first converting the ~cetone to a 'cetal, followed ~y oxidation of the pxopen~l group and then deketalizakion.
Formula II compounds wherein R2 is oxo sub-stituted alkyl serve as intermediates for preparation of oxo substitute~ alkyl derivatives having increased chain len~th via the Wittig reaction. A xepresentative proceduxe comprises, for example, reacting an appropri ate 2 (1,3-dio~olan-2-yl)alkyl triphenylphosphonium bromide at about 10C. to about 80C. with sodium dimsylate in dimethyl sulfoxide to generate the corxespond.ing ylide in situ. To the thus produced ylide is then added an appropriate reactant such as 3 lS (2-benzylox~-4-(Z-W substituted)phenyl-4-(2-oxoethyl)-cycloalXanone ethylene ketal in a suita~le solvent ~uch as dimethyl sulfoxide at a temperature of from about 10C. to about 80C. The product, a 3-(2-benzyloxy-4-(Z-W substituted)phenyl)-4-(~-oxoalk-2-enyl)cycloalkanone bis ethylene ketal, is recovered by known methods such as extraction and column chroma-tography on silica gel. In this Wittig ~eactio~, the oxo group of the cycloalkanone moiety is protected by conversion to a ketal. If desired, th~ product is subjected to acid hydrolysis to regenerate the oxo groups. However~ when the product is to be subjected t~ furthex reactions, it is advantageous to retain the bis eth~lene }cetal protecting groups on the product.
Reduction of the protec~ed t~-oxoalkenyl) group of ~he thus produced compounds using catalytic hydrogenation over a noble metal catalyst, e.g., Pd/C, affords the corres?onding protected (~-oxoalkyl) com-pound. TreatmPnt of the reduced p-oduct with aqueous acid (HCl) as described herein provides the ~-oxoalkyl derivative of formula II wherein R2 is ~-oxoalkyl. Sodium borohydride reduction of the protected compound affords a corresponding hydroxyalkyl compound wherein R2 is ~-hydroxyalkyl.
Formation of a secondary alcohol group is readily achieved by Grignard reaction on an appropriate compound of formula II, the l-oxo group of which is protected as an alkylene ketal, and in which R2 is oxoal]cyl.
Compounds of formula II wherein Y is -CHtR3)CH2- are prepared via the previously described Grignard reaction from the appropriate 5-[2-benzyloxy-~-(Z-W substituted)phenyl]-2-cycloalken-1-ones, the p~eparation of which are described in Belgian Patent 870,404, published March 12, 1979. Nucleophilic addition of the elements of HCN to said 2-cycloalken-l-one compounds by reaction thereof with aqueous sodium or potassium cyanide affords the corres-ponding trans-3-[2-benzyloxy-4-(Z-W substituted)phenyl]-5-cyano cycloalkanones which are valuable intermediates. Reduction of the oxo group of the cyclo-alkanone moiety by means of sodium borohydride yields the corresponding trans-cis hydroxy compound. It is converted to the corresponding trans-trans compound by refluxing in t-butanol solu~ion in the presence of potassium t-butoxide.
The stereoisomeric cis-3[2-benzyloxy-4-(Z-W substituted)phenyl]-cis 5-cyanocycloalkanols are prepared by oxidation of the trans-trans steroisomers using, for example, Jones' reagent followed by sodium borohydride reduction of the thus-produced cis-3-[2-benzyloxy-4-(Z-W substituted)phenyl]-5-cyanocyclo-alkanone.
Each of the above-mentioned 5-cyanocycloalkanol and cycloalkanone derivatives is also a valuable intermediate. The cyano group is readily con-verted by reduction with diisobutyl aluminum hydride (DIBAL-H) to the corres-ponding formyl derivative. The procedure comprises reacting the cyano derivative - 16 -with DIBAL-H, two equivalents, in toluene at a low temperature, e.g., 0 C.
to -65C., followed by treating the reaction with dilute acid, e.g., a mineral acid such as sulfuric acid. The formyl derivative is recovered by standard procedures such as extraction with ether and evaporation of the solvent.
Reduction of the formyl derivative, e.g., by sodium borohydride, affords the corresponding hydroxymethyl derivative. In the above reactionsthe benzyl ether derivative of the 3-(2-hydroxy-~-(Z-W substituted)phenyl)-5-cyanocycloalkanone is used as reactant in order ~o avoid reactions at the phenolic hydroxy group.
The protecting benzyl group is removed by methods described above.
The 5-formyl derivative serves as intermediates for preparing oxo substltuted alkyl derivatives having increased chain length via the Wittig reaction,as described above as regards R2.
Acyl derivatives of formula II compounds wherein Rl is hydrogen, are prepared by acylation with the appropriate alkanoic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide~ or by reac-tion with the appropriate alkanoic acid chloride or anhydride in the presence of a base such as pyridine.
The analgesic properties of the compounds of the parent application are determined by tests using nociceptive stimuli. It isnoted that compounds 2n of formula II wherein Rl is a hydroxy protecting group are not pharmacologically active for the purposes described herein but are useful as intermediates :Eor said compounds wherein Rl is hydrogen.
~ \
Tésts Using Thermal Nocice~tive Stimuli a) Mouse Hot Plate Analgesic Testing The method used is modified after Woolfe and MacDonald, J. Pharmacol. ~. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied to the feet of mice on a l/8-inch thick aluminum p]ate. A
250 watt reflector infrared heat lamp is placed under the bottom of the aluminum plate. A thermal regulator, connected to thermistors on the plate surface, programs the heat lamp to maintain a cons~ant temperature of 57C. Each mouse is dropped into a glass cylinder (6 1/2-inch diameter) resting on the hot plate, and _ 19_ ming is begun when the animal's fePt touch the plate. The mouse is observed at 0.5 and 2 hours after treatment with the test compound for the first "~licking"
movemen~s of one or both hind feet, or until 10 seconds elapse w.ithout such movementsO Morphine has an MP~50 =
~-5.6 mg./kg. (sOc.).
b) Mouse Tail ~ ng Tail flick testing in mice is modified after DtAmour and Smith, J. Phaxmacol. Exp. Ther., 72, 74~79 (1941) using controlle.d high inten~ity heat applied to the ~ail. Each mouse is placed in a snug-fit~ing metal cylinder, with the tail protruding through one end. This cylinde.r is arranged so that ~he tail lies flat over a concealed heat lamp. At the onset of testing, an aluminum flag over the lamp is drawn back, allowing the light beam to pass through the slit and focus o~to the end of ~he tail. A timer is simultaneously activated. The latency of a sudden flick of the tail is a~cer~ained~ Untreated mice usually react within
3-4 seconds after exposure to the lamp. The end point for protection is lO seconds. Each mouse is tested at O.S and 2 hours a~ter treatment with morphine and the test compound. Morphine has an MPR~o of 3.2-5.6 mgO/kg.
~s.c~ ) .
c) Tail Immersion Procedure The m~thod is a modification o the receptacle procedure developed by Benbasset, et alO, Arch. int.
Pharmacod~., 122, 434 (1959). Male albino mice tl9~21 g.) of the C~arles River CD-l strain are weighed and marked Eor identification. Five animals are normally used in each drug treatmen~ group with each animal servi~g as its own control. For general screening purposes, new tes~ agents are first administered at a dose of 56 mg.~kgO
intraperitoneally or subcutaneously, delivered in a volume of lO mL./kg~ Preceding drug treabment and at 0.5 and .
1 ~L 8 ~
2 hours post drug, each animal is placed in the cylinder.
Each cylinder is provided with holes to allow for adequa-te ventilation and is closed by a round nylon plug through which the animal's tail protrudes. Th~ cylinder is held in an upright position and the tail is completely immersed in the constant temperature waterbath (56 C.).
The endpoint for each trial is an energetic jerk or twitch of the tail coupled with ~ motor responseO In some cases, the endpoint may be less vigorous post drug.
To prevent undue tissue damage, the trial is t rminated and the tail removed from the waterhath within 10 seconds.
The response latenc~ is recorded in seconds to the nearest 0.5 second. A vehicle control and a standard of known potency are tested concurrently with screening candidates. If the activity of a test agent has not returned to baseline values at the 2-hour testing point, response latPncies are determined at 4 and 6 hours. A
final measurement is made at 24 houxs i~ activity is still observed at ~he end o the test day.
Test Using Chemical Nocice~tive Stimuli Suppression of Phenyl~enzoquinone Irritant-Induced Writhing.
Groups o~ 5 Carworth Farms CF-l mice are pretreated subcutaneously or orally with sali~e, morphine, codei~e or tha tes~ compound~ Twenty minutes (i~ treated sub-cutan~ously) or ~ifty minutes (if treated orally) later, each group is treated with intraperitoneal injection o~
phenylben~oquinone, an irritant known to produce abdominal contractions. The mice are observed for 5 minutes for ~0 the presence or absence of writhing starting 5 minutes after the in~ection o~ the irritant. MPE50's of ~he dxug pretreatments in blocking writhing are ascertained.
Te _ a Effect on the ~affner Tail Pinch Procedure A modification of the procedure of ~affner, Experimentelle Prufun~ Schmerzstillender. Deutch Med.
- - \
3 ~81~
_ 21--Wschr., 55 , 731-732 (1929) is used to ascertain ~he effect~ of the test compound on aggressive attac3cing responses elicited by a stimulus pinching the tail.
Male albino rats (50-60 g.~ of the Charles River S tSprague-Dawley~ Cb strain are used. Prior to drug treabment, and again at 0.5, 1, 2 and 3 hours after ~reatment, a Johns Hopkins 2.5-inch "bulldog'l clamp is clamped onto the xoot of the rat's tailO The end~
point at each trial is clear attacking and biting behavior directed toward the offending stimulus, with the latency Eor attack recorded in seconds. The clamp i.s removed in 30 seconds if attacking has not yet occurred~ and the latency of response is recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).
15Tests Using Electrical Nociceptive Stimuli The "Flinch-Jurnp" Test A modification of the flinch-jump procedure of Tenen, Psychopharmacolo~ia, 12, 278-28S (1968) is used for determining pain thresholds. Male albino rats ~0(175-200 g~) of the Charles River (Sprague-Dawley) CD
strain are used. Prior to receiving the drug, the eet of each rat are dipped into a 20% glycerol/saline solution. The animals are then placed in a cham~er and presen~ed with a series of l-second shocks ~o the feet ¦ 25 which are delivered in-increasing intensity at 30-second I intervals. These intensities are 0.26, 0.39, 0O52~ 0~78, l.OS, 1.31, 1.58, 1.8~, 2.13, 2.42, 2.72 and 3.04 mA.
Each animal's hehavior is xated for the presence of (a~ flincht (b) squeak and (c) jump or rapid forward mo~ement at shock onset. Single upward series of shock in~ensities are presented to each rat just prior to, and at O.S, 2, 4 and 24 hours subsequent to drug trea~ment.
Results of the above tests are recorded as percent maximum possible effect (%MPE). The ~MPE of each group is sta~istically compared to the ~MPE of the standard and the predrug controL values~ The %MPE is calculat~d as follows:
t~st time - control time ~MPE cuto~ time - control time x lO0 The compounds of this invention, when used as analgesics via oral or parenteral administration, are conveniently administered in composition form. Such compositions include a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practices. For example, they can be administered in the ~orm of tablets, pills, powders or granules containing such excipients as starch~
mil~ sugar~ certain types of clay, etc. Th~y can be administered in capsules, in admixtures with the same or equivalent excipients. They can also be administered in the form of oral suspensions, solutions, emulsio~s, syrups and elixirs which may contain flavoring and coloring agents. For oral administration of the thera-peutic agents of this invention, tablets or capsules containing from about 0.01 to ahout 100 mg. are suitable ~or most applications.
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C(CH3)2C6H13 Table II
MPE50(mg./kg,) . .. . _ . . . .. .. . .
HOIID H O~I 5 . 6 HO~ u EI OH 13 . 9 39.
HOIllll~ OH H 5. 8 ~55 NC5~_ H OH 7 . 20 HOCH 2~D H OH 1. 21 . 3 . 34 1 0 l~C ~-- - --- - - O ~--- -- - ---- 2 o 8 7 . _ _ ., .. _ . .. . ,~ _. __ The antiemetic properties of ~he compounds o formulae I a~d II are determined in unanesthetized unre-strain~d ca~s according to the pxocedure described in Proc. Soc. Exptl. Biol. and Med., 160, 437-440 (1979).
The compounds of the parent application are active antiemetics via oral and parenteral administra-tion and are conveniently administered in composition Eorm. Such compositions include a pharmaceutical carrier selected on the basis of the chosen rout.e o~
2~ administration and standard pharmaceutical practice.
Fox example, they may be administered in the form of ta~lets, pills, powders or granules containing such excipients as starch, milk sugar, certain types of clay, etc. They may be administered in capsules, in ~5 admixtures with the same or equivalent excipients.
They may also be administered in the fonm of oral suspensions, dispersions, solutions, emulsions, syrups and elixirs which may contain 1a~oring and coloring agents~ For oral administration of the 8 ~
therapeutic agents of this invention, tablets or capsules co~-taining from about 0.01 to about 100 mg.
are suitable for most applications.
Tne physician will determine the dosage which will S be most suitable for an individual patient and it will vaxy with the age, weight and response of the particular patient and ~he route of administration. Generally, however, the initial analgesic dosage in adults may range from about 0.1 to about 750 mg. per day in single or ~ divided doses. In many instances, it is not necessary -to exceed 100 mg. daily. The fa~ored oral dosage range is rom abou~ 1.0 to about 300 mg./day; the preferred dose is from about 1.0 to about 50 mg./~ay. The favored parenteral dose is from about 0~1 to about 100 mg./day;
lS the preferred range from about 0.1 to about 20 mg./day.
This invention also provides pharmaceutical composi~ions, including unit dosage forms, valuable for the use of ~he herein described compounds as analgesics and other utilities disclosed herein. The dosage form can he given in single or multiple doses, as previously noted, ~o achieve the daily dosage effective for particular utility.
The compounds (drugs) described herein can be ~ormulat~d for administration in solid or liq-lid fo~n for oral or parenteral administration. Capsules con-taining drugs ~f this invention are prepared by mixing one part by weight o~ drug with nine parts of excipient such a~ starch or milk sugar and then loading the mixture into telescoping gelatin capsules such that each capsule con~ains 100 parts of the mi.Yture. Tablets containing said compounds are prepared by compounding suitable mixtures o~ drug and standard ingredients used in prepar-ing tablets, such as starch, binders and lubricants, such that each tablet COAtai~S from 0.10 to 100 mg. of drug per tablet~
The following examples include the embodiments ofthe present invention and related compounds.
~ ~81~
~8 -~X~MPLE 1 Trans~3-~2~Benzyloxy-4-(1,1-dimethylheptyl)-phenyll-4-(2-propenyl)cyclohexanone A soiution of 73.0 g. (0.188 mole) of 1 bro~o-2-benzyloxy-4-(1,1-dimethylheptyl)benzene (BrZ') in 350 ml.
of tetrahydrofuran was slowly added to 9.0 g. ~0.375 moLe) of 70-80 mesh m~gnesium metal. ~fter a 5 minute initia-tion period the rate of addition was adjusted o as to just malntain reflux. The reaction was stirred 1.5 hours longer following completion of addition while cooling ko 25 C. The xeaction was cooled to -20 C. and 1.78 g.
(~.38 mmoles) o cuprous iodide added. The resultant mixture was stirred 5 minutes and then a solution of 25.5 g. (0.188 mole) of 4-(2 propenyl)-2-cyclohexen-1-one (enone) in 30 ml. of tetrahydrofuran added dropwise while ~he reaction temperature was maintained at about -18 C.
~dditio~al 1.78 g. (9.38 mmoles) portions of cuprou~
i~dide were added following addition of 1/3 and 2/3 of the enone reactant. The reaction was stirred 5 minutes longer at -20~ C. and ther~ added to 1000 ml. of ice cold saturated ammonium chloride. The quenched mixture was extrac~ed with 1000 ml. of ether and the organic ex tract washed twice with 500 ml. of saturated ammonium chloride, once with 500 ml. of saturated 50dium chlori-de, ~ried over magnesium sulfate and evaporated (aspirator) to an oil. ~he crude oil was purified via column chroma-togr~p'ny on 1 ~. of silica gel eluted with 20~ e~her-hexane to yield $8.3 g. (70%) of the title compound as an oil.
IR (CHC13) 1712, 1645, 1613 and 1575 cm 1.
MS lm/e) 446 (M ), 360, 354 and 91.
PMR 3CDC1 0.82 (m~ terminal mPthyl), 1 23 (s gem dimethyl), ~.7-5.1 (m, vinyl H), 5.02 ~s, benzylic methine), 5.3-6.1 (m, vinyl H~, 6.79 (d, J=2~z, Ar~, 6.82 (dd, J=~ and 2Hzt ArH) and 7.0 (d, J=8Hz, ArH).
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In like manner the following compounds were prepared from the appropriate 4-(R2-substituted-2 cycloalken-l-one (enone) in place oE the enone used above and proportionate amounts of magnesium metal, S cuprous iodide and l-bromo-2-benzyloxy-4-(1,1-dimethyl-heptyl)benzene (Br ): ~
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Cis-3-[2-Benzyloxy-4~ dimethylheptyl)phenyl3-trans-4-(2-propenyl)cyclohexanol and the trans, cis isomer To a 0 C~ solution of 14.3 g. (32.1 mmoles) of trans-3-~2-benzylox~-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)Gyclohexanone in 50 ml. of methanol was added 1.22 ~. (32.1 mmoles) of sodium borohydride. The reaction was stirred 30 minutes at 0 C. and then added to 500 mln saturated sodium chloride and 300 ml. ether~
The organic extract was washed twice with 500 ml. satu-rated sodiwm chloride, dried over magnesium sulfate and evaporated (aspirator) to an oil. The crude oil was purified via column chxomatography on 200 g. of silica gel eluted with 2.1 pentane:ether to yield in order of lS elution 1.9 g. (13%) of the trans, cls-isomer of the titl~ compound as an oil, 2.7 g. (19%) of a mixture of isomers and 7.3 g. (51~) of the title compound as an oil.
Cis 3, trans-~ isomer~
IR (C~C13) 3571, 3401, 1639, 1610 and 1572 cm ~S (m/e) 44B ~M ), 406, 363 and 91.
PMR ~CDCl 0.82 (m, terminal methylj, 1.22 (s, gem dimethyl), 2.90 (m, benzylic methine), 3.73 (m, carbinol methine), 4.6-5~1 ~m, vinyl H), 5.02 (s, benzylic methylene), 5.3-6.3 (m, vinyl H), 6.75 (d, J=2Hz, ArH), 6.75 ~dd, J=~ and 2Hz~ ArH), 6.99 (d, J-8Hz, ArH) and 7.25 (bs~ Ph).
Trans~3, cis-4 isomer:
___ _ IR (C~C13) 3559, 3401, 1639, 1608 and 1567 cm 1.
MS (m~e) 448 (M ), 433, 430, 363, 406 and 31.
PMR ~cMSl 0.82 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.30 (m, ~enzylic methine~, 4.12 lm, carbi~ol methine), 4.6-5.0 (m, vinyl H), 5.06 (s, benzylic methylene), 5.2-6.1 (m, vinyl H), 6.82 (d, J-2Hz, ArH), 6.82 (dd, J=8 and 2Hz, ArH), 7.07 (d, J=8~z, ArH) and - 7.38 (bs, Ph~.
Following the above procedure, the compounds tabulated below were prepared from appropriat~ 3-~2-benzyloxy-4-(1 f 1-dimethylheptyl)phenyl]-4-(2-R2-substitut~d)cyclo-alkanones and stoichiometric amounts of sodium boro-hydride, i.e~, one gram atom/oxo group present:
fH
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2 -C(CH3)2(CH2)5C 3.
In the ~able, R represents the 3-[2 benzyloxy-4-(l,l~dimethylheptyl)phenyl3 moie-ty~
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c) Tail Immersion Procedure The m~thod is a modification o the receptacle procedure developed by Benbasset, et alO, Arch. int.
Pharmacod~., 122, 434 (1959). Male albino mice tl9~21 g.) of the C~arles River CD-l strain are weighed and marked Eor identification. Five animals are normally used in each drug treatmen~ group with each animal servi~g as its own control. For general screening purposes, new tes~ agents are first administered at a dose of 56 mg.~kgO
intraperitoneally or subcutaneously, delivered in a volume of lO mL./kg~ Preceding drug treabment and at 0.5 and .
1 ~L 8 ~
2 hours post drug, each animal is placed in the cylinder.
Each cylinder is provided with holes to allow for adequa-te ventilation and is closed by a round nylon plug through which the animal's tail protrudes. Th~ cylinder is held in an upright position and the tail is completely immersed in the constant temperature waterbath (56 C.).
The endpoint for each trial is an energetic jerk or twitch of the tail coupled with ~ motor responseO In some cases, the endpoint may be less vigorous post drug.
To prevent undue tissue damage, the trial is t rminated and the tail removed from the waterhath within 10 seconds.
The response latenc~ is recorded in seconds to the nearest 0.5 second. A vehicle control and a standard of known potency are tested concurrently with screening candidates. If the activity of a test agent has not returned to baseline values at the 2-hour testing point, response latPncies are determined at 4 and 6 hours. A
final measurement is made at 24 houxs i~ activity is still observed at ~he end o the test day.
Test Using Chemical Nocice~tive Stimuli Suppression of Phenyl~enzoquinone Irritant-Induced Writhing.
Groups o~ 5 Carworth Farms CF-l mice are pretreated subcutaneously or orally with sali~e, morphine, codei~e or tha tes~ compound~ Twenty minutes (i~ treated sub-cutan~ously) or ~ifty minutes (if treated orally) later, each group is treated with intraperitoneal injection o~
phenylben~oquinone, an irritant known to produce abdominal contractions. The mice are observed for 5 minutes for ~0 the presence or absence of writhing starting 5 minutes after the in~ection o~ the irritant. MPE50's of ~he dxug pretreatments in blocking writhing are ascertained.
Te _ a Effect on the ~affner Tail Pinch Procedure A modification of the procedure of ~affner, Experimentelle Prufun~ Schmerzstillender. Deutch Med.
- - \
3 ~81~
_ 21--Wschr., 55 , 731-732 (1929) is used to ascertain ~he effect~ of the test compound on aggressive attac3cing responses elicited by a stimulus pinching the tail.
Male albino rats (50-60 g.~ of the Charles River S tSprague-Dawley~ Cb strain are used. Prior to drug treabment, and again at 0.5, 1, 2 and 3 hours after ~reatment, a Johns Hopkins 2.5-inch "bulldog'l clamp is clamped onto the xoot of the rat's tailO The end~
point at each trial is clear attacking and biting behavior directed toward the offending stimulus, with the latency Eor attack recorded in seconds. The clamp i.s removed in 30 seconds if attacking has not yet occurred~ and the latency of response is recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).
15Tests Using Electrical Nociceptive Stimuli The "Flinch-Jurnp" Test A modification of the flinch-jump procedure of Tenen, Psychopharmacolo~ia, 12, 278-28S (1968) is used for determining pain thresholds. Male albino rats ~0(175-200 g~) of the Charles River (Sprague-Dawley) CD
strain are used. Prior to receiving the drug, the eet of each rat are dipped into a 20% glycerol/saline solution. The animals are then placed in a cham~er and presen~ed with a series of l-second shocks ~o the feet ¦ 25 which are delivered in-increasing intensity at 30-second I intervals. These intensities are 0.26, 0.39, 0O52~ 0~78, l.OS, 1.31, 1.58, 1.8~, 2.13, 2.42, 2.72 and 3.04 mA.
Each animal's hehavior is xated for the presence of (a~ flincht (b) squeak and (c) jump or rapid forward mo~ement at shock onset. Single upward series of shock in~ensities are presented to each rat just prior to, and at O.S, 2, 4 and 24 hours subsequent to drug trea~ment.
Results of the above tests are recorded as percent maximum possible effect (%MPE). The ~MPE of each group is sta~istically compared to the ~MPE of the standard and the predrug controL values~ The %MPE is calculat~d as follows:
t~st time - control time ~MPE cuto~ time - control time x lO0 The compounds of this invention, when used as analgesics via oral or parenteral administration, are conveniently administered in composition form. Such compositions include a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practices. For example, they can be administered in the ~orm of tablets, pills, powders or granules containing such excipients as starch~
mil~ sugar~ certain types of clay, etc. Th~y can be administered in capsules, in admixtures with the same or equivalent excipients. They can also be administered in the form of oral suspensions, solutions, emulsio~s, syrups and elixirs which may contain flavoring and coloring agents. For oral administration of the thera-peutic agents of this invention, tablets or capsules containing from about 0.01 to ahout 100 mg. are suitable ~or most applications.
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C(CH3)2C6H13 Table II
MPE50(mg./kg,) . .. . _ . . . .. .. . .
HOIID H O~I 5 . 6 HO~ u EI OH 13 . 9 39.
HOIllll~ OH H 5. 8 ~55 NC5~_ H OH 7 . 20 HOCH 2~D H OH 1. 21 . 3 . 34 1 0 l~C ~-- - --- - - O ~--- -- - ---- 2 o 8 7 . _ _ ., .. _ . .. . ,~ _. __ The antiemetic properties of ~he compounds o formulae I a~d II are determined in unanesthetized unre-strain~d ca~s according to the pxocedure described in Proc. Soc. Exptl. Biol. and Med., 160, 437-440 (1979).
The compounds of the parent application are active antiemetics via oral and parenteral administra-tion and are conveniently administered in composition Eorm. Such compositions include a pharmaceutical carrier selected on the basis of the chosen rout.e o~
2~ administration and standard pharmaceutical practice.
Fox example, they may be administered in the form of ta~lets, pills, powders or granules containing such excipients as starch, milk sugar, certain types of clay, etc. They may be administered in capsules, in ~5 admixtures with the same or equivalent excipients.
They may also be administered in the fonm of oral suspensions, dispersions, solutions, emulsions, syrups and elixirs which may contain 1a~oring and coloring agents~ For oral administration of the 8 ~
therapeutic agents of this invention, tablets or capsules co~-taining from about 0.01 to about 100 mg.
are suitable for most applications.
Tne physician will determine the dosage which will S be most suitable for an individual patient and it will vaxy with the age, weight and response of the particular patient and ~he route of administration. Generally, however, the initial analgesic dosage in adults may range from about 0.1 to about 750 mg. per day in single or ~ divided doses. In many instances, it is not necessary -to exceed 100 mg. daily. The fa~ored oral dosage range is rom abou~ 1.0 to about 300 mg./day; the preferred dose is from about 1.0 to about 50 mg./~ay. The favored parenteral dose is from about 0~1 to about 100 mg./day;
lS the preferred range from about 0.1 to about 20 mg./day.
This invention also provides pharmaceutical composi~ions, including unit dosage forms, valuable for the use of ~he herein described compounds as analgesics and other utilities disclosed herein. The dosage form can he given in single or multiple doses, as previously noted, ~o achieve the daily dosage effective for particular utility.
The compounds (drugs) described herein can be ~ormulat~d for administration in solid or liq-lid fo~n for oral or parenteral administration. Capsules con-taining drugs ~f this invention are prepared by mixing one part by weight o~ drug with nine parts of excipient such a~ starch or milk sugar and then loading the mixture into telescoping gelatin capsules such that each capsule con~ains 100 parts of the mi.Yture. Tablets containing said compounds are prepared by compounding suitable mixtures o~ drug and standard ingredients used in prepar-ing tablets, such as starch, binders and lubricants, such that each tablet COAtai~S from 0.10 to 100 mg. of drug per tablet~
The following examples include the embodiments ofthe present invention and related compounds.
~ ~81~
~8 -~X~MPLE 1 Trans~3-~2~Benzyloxy-4-(1,1-dimethylheptyl)-phenyll-4-(2-propenyl)cyclohexanone A soiution of 73.0 g. (0.188 mole) of 1 bro~o-2-benzyloxy-4-(1,1-dimethylheptyl)benzene (BrZ') in 350 ml.
of tetrahydrofuran was slowly added to 9.0 g. ~0.375 moLe) of 70-80 mesh m~gnesium metal. ~fter a 5 minute initia-tion period the rate of addition was adjusted o as to just malntain reflux. The reaction was stirred 1.5 hours longer following completion of addition while cooling ko 25 C. The xeaction was cooled to -20 C. and 1.78 g.
(~.38 mmoles) o cuprous iodide added. The resultant mixture was stirred 5 minutes and then a solution of 25.5 g. (0.188 mole) of 4-(2 propenyl)-2-cyclohexen-1-one (enone) in 30 ml. of tetrahydrofuran added dropwise while ~he reaction temperature was maintained at about -18 C.
~dditio~al 1.78 g. (9.38 mmoles) portions of cuprou~
i~dide were added following addition of 1/3 and 2/3 of the enone reactant. The reaction was stirred 5 minutes longer at -20~ C. and ther~ added to 1000 ml. of ice cold saturated ammonium chloride. The quenched mixture was extrac~ed with 1000 ml. of ether and the organic ex tract washed twice with 500 ml. of saturated ammonium chloride, once with 500 ml. of saturated 50dium chlori-de, ~ried over magnesium sulfate and evaporated (aspirator) to an oil. ~he crude oil was purified via column chroma-togr~p'ny on 1 ~. of silica gel eluted with 20~ e~her-hexane to yield $8.3 g. (70%) of the title compound as an oil.
IR (CHC13) 1712, 1645, 1613 and 1575 cm 1.
MS lm/e) 446 (M ), 360, 354 and 91.
PMR 3CDC1 0.82 (m~ terminal mPthyl), 1 23 (s gem dimethyl), ~.7-5.1 (m, vinyl H), 5.02 ~s, benzylic methine), 5.3-6.1 (m, vinyl H~, 6.79 (d, J=2~z, Ar~, 6.82 (dd, J=~ and 2Hzt ArH) and 7.0 (d, J=8Hz, ArH).
o ~
- 2~
In like manner the following compounds were prepared from the appropriate 4-(R2-substituted-2 cycloalken-l-one (enone) in place oE the enone used above and proportionate amounts of magnesium metal, S cuprous iodide and l-bromo-2-benzyloxy-4-(1,1-dimethyl-heptyl)benzene (Br ): ~
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Cis-3-[2-Benzyloxy-4~ dimethylheptyl)phenyl3-trans-4-(2-propenyl)cyclohexanol and the trans, cis isomer To a 0 C~ solution of 14.3 g. (32.1 mmoles) of trans-3-~2-benzylox~-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)Gyclohexanone in 50 ml. of methanol was added 1.22 ~. (32.1 mmoles) of sodium borohydride. The reaction was stirred 30 minutes at 0 C. and then added to 500 mln saturated sodium chloride and 300 ml. ether~
The organic extract was washed twice with 500 ml. satu-rated sodiwm chloride, dried over magnesium sulfate and evaporated (aspirator) to an oil. The crude oil was purified via column chxomatography on 200 g. of silica gel eluted with 2.1 pentane:ether to yield in order of lS elution 1.9 g. (13%) of the trans, cls-isomer of the titl~ compound as an oil, 2.7 g. (19%) of a mixture of isomers and 7.3 g. (51~) of the title compound as an oil.
Cis 3, trans-~ isomer~
IR (C~C13) 3571, 3401, 1639, 1610 and 1572 cm ~S (m/e) 44B ~M ), 406, 363 and 91.
PMR ~CDCl 0.82 (m, terminal methylj, 1.22 (s, gem dimethyl), 2.90 (m, benzylic methine), 3.73 (m, carbinol methine), 4.6-5~1 ~m, vinyl H), 5.02 (s, benzylic methylene), 5.3-6.3 (m, vinyl H), 6.75 (d, J=2Hz, ArH), 6.75 ~dd, J=~ and 2Hz~ ArH), 6.99 (d, J-8Hz, ArH) and 7.25 (bs~ Ph).
Trans~3, cis-4 isomer:
___ _ IR (C~C13) 3559, 3401, 1639, 1608 and 1567 cm 1.
MS (m~e) 448 (M ), 433, 430, 363, 406 and 31.
PMR ~cMSl 0.82 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.30 (m, ~enzylic methine~, 4.12 lm, carbi~ol methine), 4.6-5.0 (m, vinyl H), 5.06 (s, benzylic methylene), 5.2-6.1 (m, vinyl H), 6.82 (d, J-2Hz, ArH), 6.82 (dd, J=8 and 2Hz, ArH), 7.07 (d, J=8~z, ArH) and - 7.38 (bs, Ph~.
Following the above procedure, the compounds tabulated below were prepared from appropriat~ 3-~2-benzyloxy-4-(1 f 1-dimethylheptyl)phenyl]-4-(2-R2-substitut~d)cyclo-alkanones and stoichiometric amounts of sodium boro-hydride, i.e~, one gram atom/oxo group present:
fH
.~
2 -C(CH3)2(CH2)5C 3.
In the ~able, R represents the 3-[2 benzyloxy-4-(l,l~dimethylheptyl)phenyl3 moie-ty~
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~-~o - -EX~MPLE 3 Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-trans-~-hydroxymethylcyclohexanol Using the procedure of Example 2, 1.0 g. (2.29 mmole) of CiS-3- [2-benzyloxy-~-(1,1-dimethylheptylJphenyl)-trans-4-oxomethylcyclohexanol is reduced to give a quantitative yield of the ti-tle compound as an oilO
IR (CHC13) 3400, 1605 and 1562 cm 1.
MS (m/e) 438 (M ), 420, 353, 330, 312, 299 and 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.23 (s, gem ~imethyl), 3.25 (m, hydroxymethylene), 3.65 (m, carbinol methine), 5.08 (s, benzylic methylene), 6.90 (m, ArH), 7.12 ~d, J=8Hz~ ArH) and 7.39 ~s, Ph).
Trans-3-[2-8enzyLoxy-4~ dimethylheptyl)phenyl]~
_4-(2-hydroxyethyl)cyclohexanone et~ylene ketal Using the procedure o~ Example 2, 1.00 g. (2.03 mmole~
of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-oxoethyl)cyclohexanone ethylene ketal is reduced to give a quantitative yield of the title compound as an oil.
PMR ~cDMsl 0.82 (m, terminal methylj, 1.11 (s, gem dimethyl), 3.50 (bt, J-6Hz, alcohol methylene), 3.91 (s, ethylene), 5102 (s, benzylic methylene) t 6.8 7.1 (m, ArH) and 7.33 (m, PhH).
~0 t.~
-Cis-3-~2-Benzyloxy~4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol To a mechanically stirred, 0C. solution of 2.0 g.
(4.46 mmoles) of cis~3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-trans-4-(2-propenyl)cyclohexanol in 20 ml. of tetrahydrofuran was added 9 ml. (8.92 mmoles) of b~ran tetrahydrofuran complex (lM in tetrahydrofuran~. The reaction was allowed to warm to 25~ C. and was then stirred ~or 30 minutes at 25 C. The reaction was cooled to 0 C. and oxidized by the addition of 1 ml~ water~
2.66 ml. (5.34 mmoles) of 2N sodium hydroxide and 0.92 ml.
(10.7 mmoles) of 30% hydrogen peroxide. The reaction was allowed to warm to 25 C., stirred for 35 minutes~
L5 and added to 200 ml. saturated sodium chloride and 200 ml.
ether. The ether extract was washed twice with 100 ml.
of sa urated sodium chloride, dried over magnesium sulfate and evaporated (aspirator) to an oil~ The crude oil was purified via column chromatography on 40 g. of silica gel, eluted with ether to yield 2.0 g. (96%) of the title compound as an oil~
IR (CHC13) 3623, 3425, 1623 and 1580 cm 1 MS (m/e) 466 (M ), 448, 381, 363, 358, 357 and 91~
CDC13 0.82 (m, terminal methyl), 1 24 (s gem 2S dimethyl), 2.90 (m, benzylic methine), 3.2-3.9 (m, carbinol methine and methylene), 5.08 (s, benzylic methylene), 6.86 ~d, J=2Hz/ ArH), 6.86 ~dd, J=8 and 2Hz, ArH) and 7.05 (d, J=8Hz, ArH).
~fJ
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_42-In like manner the following compounds are prepared rom appropriate reactants.
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Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl~
trans-4-(3-hydroxypropyl)cyclohexanGl A mixture of 2.0 g. (4.29 mmole) of ClS~-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans= 4-(3-hydroxypropyl)cyclohexanol and 300 mg. of 5~ Pd/C/50%
water in 10 ml. o ethanol was stirred under 1 atmosphere of hydrogen gas for 45 minutes at room temperature.
The reaction was filtered through diatomaceous earth and the fil~rate evaporated under reduced pressuxe to a solid~ Recrystallization of the crude solid product from diisopropyl ether gave 1.41 g. (94%~ of the title compolmd .
m.p.: 132-3 C. (diisopropyl ether)~
IR (KBr) 3448, 3226, 1626 and 1592 cm 1~
MS (m/e) 376 (M ), 358, 304, 291 and 273.
P~R (CDC13, D20, D6-DMSO) ~ 0~83 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.39 (t, J=6Hz, oarbinol methylene), 3.64 (ml carbinol methine), 6.85 (m, ArH) and 6.91 (d, J=8H~, ArH~.
Analysis: Calc'dO for C24H40O3 C, 76.55; H, 10.71.
Found: C, 76.55; H, 10.44.
Similarly, the following compounds are prepared from appropriate ben~yl ether reactants:
A B
( ~ OH
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~-~o - -EX~MPLE 3 Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-trans-~-hydroxymethylcyclohexanol Using the procedure of Example 2, 1.0 g. (2.29 mmole) of CiS-3- [2-benzyloxy-~-(1,1-dimethylheptylJphenyl)-trans-4-oxomethylcyclohexanol is reduced to give a quantitative yield of the ti-tle compound as an oilO
IR (CHC13) 3400, 1605 and 1562 cm 1.
MS (m/e) 438 (M ), 420, 353, 330, 312, 299 and 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.23 (s, gem ~imethyl), 3.25 (m, hydroxymethylene), 3.65 (m, carbinol methine), 5.08 (s, benzylic methylene), 6.90 (m, ArH), 7.12 ~d, J=8Hz~ ArH) and 7.39 ~s, Ph).
Trans-3-[2-8enzyLoxy-4~ dimethylheptyl)phenyl]~
_4-(2-hydroxyethyl)cyclohexanone et~ylene ketal Using the procedure o~ Example 2, 1.00 g. (2.03 mmole~
of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-oxoethyl)cyclohexanone ethylene ketal is reduced to give a quantitative yield of the title compound as an oil.
PMR ~cDMsl 0.82 (m, terminal methylj, 1.11 (s, gem dimethyl), 3.50 (bt, J-6Hz, alcohol methylene), 3.91 (s, ethylene), 5102 (s, benzylic methylene) t 6.8 7.1 (m, ArH) and 7.33 (m, PhH).
~0 t.~
-Cis-3-~2-Benzyloxy~4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol To a mechanically stirred, 0C. solution of 2.0 g.
(4.46 mmoles) of cis~3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-trans-4-(2-propenyl)cyclohexanol in 20 ml. of tetrahydrofuran was added 9 ml. (8.92 mmoles) of b~ran tetrahydrofuran complex (lM in tetrahydrofuran~. The reaction was allowed to warm to 25~ C. and was then stirred ~or 30 minutes at 25 C. The reaction was cooled to 0 C. and oxidized by the addition of 1 ml~ water~
2.66 ml. (5.34 mmoles) of 2N sodium hydroxide and 0.92 ml.
(10.7 mmoles) of 30% hydrogen peroxide. The reaction was allowed to warm to 25 C., stirred for 35 minutes~
L5 and added to 200 ml. saturated sodium chloride and 200 ml.
ether. The ether extract was washed twice with 100 ml.
of sa urated sodium chloride, dried over magnesium sulfate and evaporated (aspirator) to an oil~ The crude oil was purified via column chromatography on 40 g. of silica gel, eluted with ether to yield 2.0 g. (96%) of the title compound as an oil~
IR (CHC13) 3623, 3425, 1623 and 1580 cm 1 MS (m/e) 466 (M ), 448, 381, 363, 358, 357 and 91~
CDC13 0.82 (m, terminal methyl), 1 24 (s gem 2S dimethyl), 2.90 (m, benzylic methine), 3.2-3.9 (m, carbinol methine and methylene), 5.08 (s, benzylic methylene), 6.86 ~d, J=2Hz/ ArH), 6.86 ~dd, J=8 and 2Hz, ArH) and 7.05 (d, J=8Hz, ArH).
~fJ
4 0 ~
_42-In like manner the following compounds are prepared rom appropriate reactants.
~>
A B O
~ C(cH3)~(cH2~5c~3 t) ~
._ ___ . . ~
I co o ~ I I ~
rl O ~ I ~ ~ ~ O I ~ O S ~
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E~ t~ `~ ~ ~ ~ h ~o ~ 4 ~ I N ~ ¢
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~ U~
___ __ _ _ r~~
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I ~ O ~ ~ O ~
_ __ ___ _ ~ .,~ ~ ~ .,~ ~ ~
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h r-i i ri r~i h U^i C~
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~\i o ~ ~
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1~-~ ~",'''- - . . . .
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Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl~
trans-4-(3-hydroxypropyl)cyclohexanGl A mixture of 2.0 g. (4.29 mmole) of ClS~-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans= 4-(3-hydroxypropyl)cyclohexanol and 300 mg. of 5~ Pd/C/50%
water in 10 ml. o ethanol was stirred under 1 atmosphere of hydrogen gas for 45 minutes at room temperature.
The reaction was filtered through diatomaceous earth and the fil~rate evaporated under reduced pressuxe to a solid~ Recrystallization of the crude solid product from diisopropyl ether gave 1.41 g. (94%~ of the title compolmd .
m.p.: 132-3 C. (diisopropyl ether)~
IR (KBr) 3448, 3226, 1626 and 1592 cm 1~
MS (m/e) 376 (M ), 358, 304, 291 and 273.
P~R (CDC13, D20, D6-DMSO) ~ 0~83 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.39 (t, J=6Hz, oarbinol methylene), 3.64 (ml carbinol methine), 6.85 (m, ArH) and 6.91 (d, J=8H~, ArH~.
Analysis: Calc'dO for C24H40O3 C, 76.55; H, 10.71.
Found: C, 76.55; H, 10.44.
Similarly, the following compounds are prepared from appropriate ben~yl ether reactants:
A B
( ~ OH
~ ~ -C5cH3)2(cH2)5cH3 (The value of R2 is the same in reactant and product).
3 ~
---- ~ -- --~ ~ t~ o l oo ~ o l ~ oo o ~ o r~ ~ ~ r~ ~ ~ ~ ~ r ~ . ~ ~> I~
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^ ~ O
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__ ." ~ , 0 ~1 E~PLE 7 Trans-3-t2~Benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-4-(2-propenyl)cyclohexanone ethylene ketal ~ mi~ture of 17.0 g. (38.1 mmoles) of trans-3-[2 benzyloxy-4-~L,l-dimethylheptyl)phenyl]-4-(2-propenyl)-cyclohexanone, 47.2 g. (0.762 mole) ethylene glycol and 250 mg. of ~-toluenesulfonic acid monohydrate in 200 ml.
of benzene was heated at reflux for 3 hours with a Dean-Stark trap. The reaction was cooled and added to 200 ml~
lN sodium hydroxide, 100 ml. ether and 100 ml. pentane.
-The organic extract was washed twice with 200 ml. portionsof water, twice with 200 ml. portions of saturated sodium chloride, dried over magnesium sul~ate and evaporated (aspirator) giving a quantitative yield of the title compound.
IR (CHC13) 1656, 1626 and 1587 cm 1.
MS (m/e) 490 (M ), 475, 450, 449, 448, 446, 407, 405, 399, 383 and 91.
PMR ~qMcl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.1 ~m, benzylic methine), 3.90 (s, ethylene ketal), 4.6~5.0 and 5.2-6.0 (m, ~inyl H), 5.07 (s, benzylic methyLene), 6.81 (d, J=2Hz, ArH~, 6.81 (dd, J=8 and 2Hz, ArH) and 7.02 (d, J=8Hz, ArH).
In like manner, 4.5 g. (9.8 mmole~ of txans-3-[2-benzyloxy~4-(1,1-dimethylheptyl)phenyl3-4-(2-propenyl)-CycloheptanQ~e i5 converted in ~uantitative yieLd to trans-3-~2 ben2yloxy-4-(l,l-dimethylheptyl)phenyl]-4 -2-propenyl)cycloheptanone ethylene ketal, an oil.
IR (CHC13) 1650, 1613, 1550, 1504 and 1460 cm 1 ~S (m/e) 504 (M+) PMR ~CDCl 0.80 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.20 (m, benzylic methine), 3.80 (bs, ethylene), .6-6.0 (m, olefinic), 5.07 (s, benzylic methylene),
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__ ." ~ , 0 ~1 E~PLE 7 Trans-3-t2~Benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-4-(2-propenyl)cyclohexanone ethylene ketal ~ mi~ture of 17.0 g. (38.1 mmoles) of trans-3-[2 benzyloxy-4-~L,l-dimethylheptyl)phenyl]-4-(2-propenyl)-cyclohexanone, 47.2 g. (0.762 mole) ethylene glycol and 250 mg. of ~-toluenesulfonic acid monohydrate in 200 ml.
of benzene was heated at reflux for 3 hours with a Dean-Stark trap. The reaction was cooled and added to 200 ml~
lN sodium hydroxide, 100 ml. ether and 100 ml. pentane.
-The organic extract was washed twice with 200 ml. portionsof water, twice with 200 ml. portions of saturated sodium chloride, dried over magnesium sul~ate and evaporated (aspirator) giving a quantitative yield of the title compound.
IR (CHC13) 1656, 1626 and 1587 cm 1.
MS (m/e) 490 (M ), 475, 450, 449, 448, 446, 407, 405, 399, 383 and 91.
PMR ~qMcl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.1 ~m, benzylic methine), 3.90 (s, ethylene ketal), 4.6~5.0 and 5.2-6.0 (m, ~inyl H), 5.07 (s, benzylic methyLene), 6.81 (d, J=2Hz, ArH~, 6.81 (dd, J=8 and 2Hz, ArH) and 7.02 (d, J=8Hz, ArH).
In like manner, 4.5 g. (9.8 mmole~ of txans-3-[2-benzyloxy~4-(1,1-dimethylheptyl)phenyl3-4-(2-propenyl)-CycloheptanQ~e i5 converted in ~uantitative yieLd to trans-3-~2 ben2yloxy-4-(l,l-dimethylheptyl)phenyl]-4 -2-propenyl)cycloheptanone ethylene ketal, an oil.
IR (CHC13) 1650, 1613, 1550, 1504 and 1460 cm 1 ~S (m/e) 504 (M+) PMR ~CDCl 0.80 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.20 (m, benzylic methine), 3.80 (bs, ethylene), .6-6.0 (m, olefinic), 5.07 (s, benzylic methylene),
6.85 ~m, ArH), 7.02 (d, J=8~z, ArH) and 7.38 (m, Ph~).
0 ~
The following compounds are prepared from ap-propriate cycloalkanone reactants in like manner:
( ~ Q
... . .~ .
s ~2 ~ R21l _ ____ 1 -CH2 CHaCH2 CH3 ~(CH3)~(CH2)5CH3 2 -CH2-CH=CH2 H OCH(C~3)(~H~)3C6H5 2 ~CH2-CH=CH~ H C(CH3)2~CH2)5CH3 4 0 ~
Trans-3-[4-(1,1-Dim thylheptyl)-2-hydroxyphenyl]~
4-(3~hydroxypropyl)cyclohexanon_ _ A mixture of 4.0 g~ (9.56 mmvles) of trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-hydroxypropyl)-cyclohexanone ethylene ketal, 50 ml. of 2N hydrochloric acid and 100 ml. of tetrahydrofuran was heated at reflux for 2 hours. The reactisn was cooled and added to 500 ml.
saturated sodium chloride and 250 ml. ether. The ether extract was separated and washed once with 500 mlO
saturated sodium chloride, once with 500 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator~ to an oil. The crude o.il was purified via column chromatography on 200 g. of silica gel eluted with 80% ether-hexane to yield 2.93 g. ~82~) of the title compound as an oil.
IR ~CHC13) 3521, 3333, 1709, 1616 and 1567 cm 1.
MS (m/e) 374 (M ), 356, 289, 273, 247, 203 a~d 161.
PMR ~CDCl 0.82 (m, ~erminal methyl), 1.28 (s, gem dimethyl), 3.76 (m, alcohol methylene), 6.8 (m, ArH) and 6.99 (d, ~-8H~, ArH).
In like manner the following compounds are prepared from appropriate ketals:
' (P~ IORl ~ --C(CH3)2(C~I2)5CH3 I
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4 0 d2 Trans-3-[2-Benzyloxy-4-(1,1 dimethylheptyl)-phenyL~-4-(2-oxoethyl)cycloh~xanone ~th~lene ketal ~ mixture of L7.0 g. (34~7 mmoles) o~ trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)-cyclohexanone ethylene ketal, 44.5 g. (0.208 ~nole~ of sodium metaperiodate and 176 mgO (0.69 mmole) of osmium tetroxide in 340 ml. tetrahydrofuran and 100 ml. of water was stirred at room temperature for 3.5 hours. The reaction mixture was then added to 1000 ml. 15% sodium sulfite-1000 ml. ether. The organic phase was separated, washed twice with S00 ml~ of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator).
The residue was purified by column chromatography on lS ~00 g. of silica gel eluted with 33-75~ ether petroleum ether to yield lOo O g~ (59~) Of the title compound as an oil.
IR (CHC13) 1730, 1621 and 1577 cm 1.
MS (m/e) 492 (M ), 464, 448, 407, 401, 357, 339, 332, 319, 317, 271 and 91.
p~ ~TMSl 0.83 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.~ ~m, benzylic methine), 3.94 ~s, ethylene ketal), 5.10 (s, benzylic methylene), 6.85 (dd, J-8 and 2Hz, ArH), 6.R5 (d, J=2H~, ArH), 7.07 (d, J=8Hz, ArH) and 2S 9~57 (t, J=l.SHz~ CHO).
Further elution ~ave 5.53 g~ o a mixture of two compounds~ This mixture was dissolved in 500 ml. of ether and washed with four 250 ml. portions of lN sodium hydroxide. The ether phase was dried over magnesium sulfate and evaporated (aspirator~ to yield 2.7 g. of oil. This oil was further purified via column chroma-tography on 100 g. of silica gel eluted with S0~ ether-pentane to yield 2.16 g. (12%) of trans-3-[2-benzyloxy~
4-(1,1-dime~hylheptyl) ?henvl] -4-(3-hydro~ 2-oxopropyl)-cyclohe~anone ethylene ketal as an oil. The basic extract .
~o --from a~ove was acidified with ice cold 6N hydrochloric acid and th~n extracted with 500 ml. of ether. The ether e~tract was washed twice with 200 ml. water, once with 100 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated to give 2.4 g. of oil which was purified by column chromatography on 100 g.
of silica gel eluted with 33~ ethyl acetate-pentane to yield 1.51 g. (9~ of trans-3-[2-benzyloxy-4-(1,1-dLmethylheptyl)phenyl]-4-(2-carboxymethyl)cyclohexanone ethvlene ketal.
Trans-3-[2-benæyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxy-2-oxopropyl)cyclohexanone ethylene ketal:
IR (CHC13) 3484, 1724, 1613 and 1575 cm 1.
MS tm~e) 522 (M ), 491, 448, 432, 407, 358, 99, 91 and 86.
CDC13 0.82 (terminal methyl), 1.~2 (s gem dimethyl), 2.17 (m, methylene to ketone), 2.88 (t, J=5Hz, OH), 3.82 (d, overlaps 3.90), 3.90 (s, ethylene), 5.08 (s, benzylic methylene), 6.83 (m, ArH), 7.02 (d, J=8Hæ, ArH) and 7.40 (m, PhH).
Trans~3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-~2-carboxymethyl)cyclohexanone ethylene ketal:
IR (CHC13) 3636-2273 (broad), 1724, 1621 and 1582 cm MS (m/e) 508 (M ), 449, 424, 418, 408, 402, 99, 91 and 86.
PMR ~cMSl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl~, 3.2 (m, benzylic methine), 3.93 (s, ethylene), 5.10 (s, benzylic methylene), 6.85 (m, ArH), 7.10 (d, J=8Hz, ArH) and 7.41 (m, PhH).
SLmilarly, oxidation of 2.Z0 g. (5.80 mmole) of cis-3- ~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)cyclohexanol gave 1.4 g. (54~) of ClS-3- [2-~enzyloxy-4- (l,1-dimethylheptyl)phenyl]-trans-4-(?-oxoethyl)cyclohexanol; 409 mg. (15%) of , ) 4 _ 61-_s-3-[2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroYy-2-oxopropyl)cyclohexanol and 120 mg. (4.9%) of cls-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(carboxymethyl)cyclohexanol.
2-Oxoethyl compound^
IR (CHCl~) 3610, 3425, 1623 and 1582 cm 1.
MS (m/e~ 450 (M ), 422, 405, 365, 359, 342 and 91.
PMR ~CDCl 0.82 (mr terminal methyl~ r 1.23 (5~ gem dimethyl), 3.00 (m, benzylic methine), 3.70 (m, carbinol methine), 5O09 (s, benzylic methylene), 6.88 (d, J=2Hz, ArH), 6.88 (dd, J=8 and 2Hz, ArH), 7.10 (d, J=8Hz, ArH~,
0 ~
The following compounds are prepared from ap-propriate cycloalkanone reactants in like manner:
( ~ Q
... . .~ .
s ~2 ~ R21l _ ____ 1 -CH2 CHaCH2 CH3 ~(CH3)~(CH2)5CH3 2 -CH2-CH=CH2 H OCH(C~3)(~H~)3C6H5 2 ~CH2-CH=CH~ H C(CH3)2~CH2)5CH3 4 0 ~
Trans-3-[4-(1,1-Dim thylheptyl)-2-hydroxyphenyl]~
4-(3~hydroxypropyl)cyclohexanon_ _ A mixture of 4.0 g~ (9.56 mmvles) of trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-hydroxypropyl)-cyclohexanone ethylene ketal, 50 ml. of 2N hydrochloric acid and 100 ml. of tetrahydrofuran was heated at reflux for 2 hours. The reactisn was cooled and added to 500 ml.
saturated sodium chloride and 250 ml. ether. The ether extract was separated and washed once with 500 mlO
saturated sodium chloride, once with 500 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator~ to an oil. The crude o.il was purified via column chromatography on 200 g. of silica gel eluted with 80% ether-hexane to yield 2.93 g. ~82~) of the title compound as an oil.
IR ~CHC13) 3521, 3333, 1709, 1616 and 1567 cm 1.
MS (m/e) 374 (M ), 356, 289, 273, 247, 203 a~d 161.
PMR ~CDCl 0.82 (m, ~erminal methyl), 1.28 (s, gem dimethyl), 3.76 (m, alcohol methylene), 6.8 (m, ArH) and 6.99 (d, ~-8H~, ArH).
In like manner the following compounds are prepared from appropriate ketals:
' (P~ IORl ~ --C(CH3)2(C~I2)5CH3 I
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4 0 d2 Trans-3-[2-Benzyloxy-4-(1,1 dimethylheptyl)-phenyL~-4-(2-oxoethyl)cycloh~xanone ~th~lene ketal ~ mixture of L7.0 g. (34~7 mmoles) o~ trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)-cyclohexanone ethylene ketal, 44.5 g. (0.208 ~nole~ of sodium metaperiodate and 176 mgO (0.69 mmole) of osmium tetroxide in 340 ml. tetrahydrofuran and 100 ml. of water was stirred at room temperature for 3.5 hours. The reaction mixture was then added to 1000 ml. 15% sodium sulfite-1000 ml. ether. The organic phase was separated, washed twice with S00 ml~ of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator).
The residue was purified by column chromatography on lS ~00 g. of silica gel eluted with 33-75~ ether petroleum ether to yield lOo O g~ (59~) Of the title compound as an oil.
IR (CHC13) 1730, 1621 and 1577 cm 1.
MS (m/e) 492 (M ), 464, 448, 407, 401, 357, 339, 332, 319, 317, 271 and 91.
p~ ~TMSl 0.83 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.~ ~m, benzylic methine), 3.94 ~s, ethylene ketal), 5.10 (s, benzylic methylene), 6.85 (dd, J-8 and 2Hz, ArH), 6.R5 (d, J=2H~, ArH), 7.07 (d, J=8Hz, ArH) and 2S 9~57 (t, J=l.SHz~ CHO).
Further elution ~ave 5.53 g~ o a mixture of two compounds~ This mixture was dissolved in 500 ml. of ether and washed with four 250 ml. portions of lN sodium hydroxide. The ether phase was dried over magnesium sulfate and evaporated (aspirator~ to yield 2.7 g. of oil. This oil was further purified via column chroma-tography on 100 g. of silica gel eluted with S0~ ether-pentane to yield 2.16 g. (12%) of trans-3-[2-benzyloxy~
4-(1,1-dime~hylheptyl) ?henvl] -4-(3-hydro~ 2-oxopropyl)-cyclohe~anone ethylene ketal as an oil. The basic extract .
~o --from a~ove was acidified with ice cold 6N hydrochloric acid and th~n extracted with 500 ml. of ether. The ether e~tract was washed twice with 200 ml. water, once with 100 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated to give 2.4 g. of oil which was purified by column chromatography on 100 g.
of silica gel eluted with 33~ ethyl acetate-pentane to yield 1.51 g. (9~ of trans-3-[2-benzyloxy-4-(1,1-dLmethylheptyl)phenyl]-4-(2-carboxymethyl)cyclohexanone ethvlene ketal.
Trans-3-[2-benæyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxy-2-oxopropyl)cyclohexanone ethylene ketal:
IR (CHC13) 3484, 1724, 1613 and 1575 cm 1.
MS tm~e) 522 (M ), 491, 448, 432, 407, 358, 99, 91 and 86.
CDC13 0.82 (terminal methyl), 1.~2 (s gem dimethyl), 2.17 (m, methylene to ketone), 2.88 (t, J=5Hz, OH), 3.82 (d, overlaps 3.90), 3.90 (s, ethylene), 5.08 (s, benzylic methylene), 6.83 (m, ArH), 7.02 (d, J=8Hæ, ArH) and 7.40 (m, PhH).
Trans~3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-~2-carboxymethyl)cyclohexanone ethylene ketal:
IR (CHC13) 3636-2273 (broad), 1724, 1621 and 1582 cm MS (m/e) 508 (M ), 449, 424, 418, 408, 402, 99, 91 and 86.
PMR ~cMSl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl~, 3.2 (m, benzylic methine), 3.93 (s, ethylene), 5.10 (s, benzylic methylene), 6.85 (m, ArH), 7.10 (d, J=8Hz, ArH) and 7.41 (m, PhH).
SLmilarly, oxidation of 2.Z0 g. (5.80 mmole) of cis-3- ~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)cyclohexanol gave 1.4 g. (54~) of ClS-3- [2-~enzyloxy-4- (l,1-dimethylheptyl)phenyl]-trans-4-(?-oxoethyl)cyclohexanol; 409 mg. (15%) of , ) 4 _ 61-_s-3-[2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroYy-2-oxopropyl)cyclohexanol and 120 mg. (4.9%) of cls-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(carboxymethyl)cyclohexanol.
2-Oxoethyl compound^
IR (CHCl~) 3610, 3425, 1623 and 1582 cm 1.
MS (m/e~ 450 (M ), 422, 405, 365, 359, 342 and 91.
PMR ~CDCl 0.82 (mr terminal methyl~ r 1.23 (5~ gem dimethyl), 3.00 (m, benzylic methine), 3.70 (m, carbinol methine), 5O09 (s, benzylic methylene), 6.88 (d, J=2Hz, ArH), 6.88 (dd, J=8 and 2Hz, ArH), 7.10 (d, J=8Hz, ArH~,
7.40 (s, PhH) and 9.53 (t, J=1.5~z, CHO).
~-Hydroxy ketone:
IR (C~C13) 3448, 1721, 1618 and 1580 cm 1.
MS (m/e) 480 (M ), 466, 450, 449, 406 and 91.
PM~ ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.75 (m, carbinol methine), 3.86 (bs, hydroxy-methylene), 5.08 (s, benzylic methylene), 6.95 ~m, ArH), 7.05 ~d, J=8Hz, ArH) and 7.38 ts, PhH).
Acid:
Rf - 0.32 (0.25 mm, silica gel ether).
In like manner, 3,4-trans, 4,5-trans-3-[2-benzyl-oxy-4-(1,1-dimethylkeptyl)phenyl]~5-methyl-4-(2-pro-penyl)cyclohexanone ethylene ketal is oxidized to the coxresponding 4-(2-oxoethyl)cyclohexanone derivative.
Also produced are the corresponding 4-(3-hydroxy-2-oxopropyl)- and the 4-(2-carboxymethyl)cyclohexanone derivativesl -62_ EXAMPLE_l0 Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5-oxopent-Z enyl)cyclohexanone b~s ethylene ketal To a 15 C. solution of 4.05 mmole of sodium dimsylate in 6 ml. of dimethyi sulfoxide is added 1.61 g.
~4.05 mmole) of 2-(1,3-dioxolan-2-yl)ethyltriphenylphos-phonium bromide. The reaction mixture was stirred for 15 minutes and then a solution of 1~0 g. (2.03 mmole~ of tr_ns-3-~2-benzyloxy-4-(1,1-dlmethylheptyl)phenyl]-4-(2-oxoethyl)cyclohexanone ethylene ketal in one ml~ of dimethyl sulfoxide was added. The reaction was stirred for 10 minutes and then added to a mixture o 200 ml.
saturated sodium chloride and 200 ml. ether with stirring.
The ether phase was separated and washed twice with 200 ml.
of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified via column chromatography on 60 g. of silica gel eluted with 30% ether-pentane to yield 359 mg. (31~) of the title compound as an oil.
IR (C~C13) 1600 and 1563 cm 1 MS tm~e~ 576 (M )O
PMR ~CDCl 0.82 (m, terminal methylj, 1.24 (s, gem dimethyl), 2.25 ~m, methylene), 3.2 (m, benzylic methine), 3.85 (m, ethylenes), 4.80 (t, J=5Hz, dioxolane methine), 5.08 (s, benzylic methylene), 5.42 (m, olefinic ~I), 6.85 (m, ArH), 7.09 (d, J=8Hz, ArH) and 7.4 (m, PhH).
In like manner, 3,4-trans, 4,5-trans-3-[2-benzyl-oxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-(2 oxoethyl)cyclohexanone ethylene ketal and cis-3-[2-benzyloxy-4-(R)-(l-methyl-4-phenylbutoxy)phenyl]-4-trans-(2-oxoethyl)cycloheptanone ethylene ketal are converte~ to the corresponding 4-(5-oxopent-2-enyl)-bis ethylene ketals~
Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5-oxopentyl)cyclohexanone bis ethylene ketal A mixture of 520 mg. (0.902 mmole~ of trans-3-~2~
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5-oxopent-2-enyl)cyclohexanone bis ethylene ketal and 100 mg. of 5% Pd/C/50~ water in 15 ml. of ethanol was stirred under cne a~mosphere of hydrogen gas until one equivalent of hydrogen was absorbed. The reaction was filtered through l.0 diatom~ceous earth and evaporated to give a quantitative yield of thé title compound as an oil.
P~R ~cDsl 0.80 (m, terminal methyl), 1.32 (s, gem dimethyl), 3.9 (m~ ethylenes), 4.78 (m, dioxolane methine), 5.08 ~s, benzylic methylene), 6.85 (m, ArH), 7.08 (d, 3=8Hz, ArH) and 7.42 (m, PhH).
Deketalization according to the procedure of Example
~-Hydroxy ketone:
IR (C~C13) 3448, 1721, 1618 and 1580 cm 1.
MS (m/e) 480 (M ), 466, 450, 449, 406 and 91.
PM~ ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.75 (m, carbinol methine), 3.86 (bs, hydroxy-methylene), 5.08 (s, benzylic methylene), 6.95 ~m, ArH), 7.05 ~d, J=8Hz, ArH) and 7.38 ts, PhH).
Acid:
Rf - 0.32 (0.25 mm, silica gel ether).
In like manner, 3,4-trans, 4,5-trans-3-[2-benzyl-oxy-4-(1,1-dimethylkeptyl)phenyl]~5-methyl-4-(2-pro-penyl)cyclohexanone ethylene ketal is oxidized to the coxresponding 4-(2-oxoethyl)cyclohexanone derivative.
Also produced are the corresponding 4-(3-hydroxy-2-oxopropyl)- and the 4-(2-carboxymethyl)cyclohexanone derivativesl -62_ EXAMPLE_l0 Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5-oxopent-Z enyl)cyclohexanone b~s ethylene ketal To a 15 C. solution of 4.05 mmole of sodium dimsylate in 6 ml. of dimethyi sulfoxide is added 1.61 g.
~4.05 mmole) of 2-(1,3-dioxolan-2-yl)ethyltriphenylphos-phonium bromide. The reaction mixture was stirred for 15 minutes and then a solution of 1~0 g. (2.03 mmole~ of tr_ns-3-~2-benzyloxy-4-(1,1-dlmethylheptyl)phenyl]-4-(2-oxoethyl)cyclohexanone ethylene ketal in one ml~ of dimethyl sulfoxide was added. The reaction was stirred for 10 minutes and then added to a mixture o 200 ml.
saturated sodium chloride and 200 ml. ether with stirring.
The ether phase was separated and washed twice with 200 ml.
of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified via column chromatography on 60 g. of silica gel eluted with 30% ether-pentane to yield 359 mg. (31~) of the title compound as an oil.
IR (C~C13) 1600 and 1563 cm 1 MS tm~e~ 576 (M )O
PMR ~CDCl 0.82 (m, terminal methylj, 1.24 (s, gem dimethyl), 2.25 ~m, methylene), 3.2 (m, benzylic methine), 3.85 (m, ethylenes), 4.80 (t, J=5Hz, dioxolane methine), 5.08 (s, benzylic methylene), 5.42 (m, olefinic ~I), 6.85 (m, ArH), 7.09 (d, J=8Hz, ArH) and 7.4 (m, PhH).
In like manner, 3,4-trans, 4,5-trans-3-[2-benzyl-oxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-(2 oxoethyl)cyclohexanone ethylene ketal and cis-3-[2-benzyloxy-4-(R)-(l-methyl-4-phenylbutoxy)phenyl]-4-trans-(2-oxoethyl)cycloheptanone ethylene ketal are converte~ to the corresponding 4-(5-oxopent-2-enyl)-bis ethylene ketals~
Trans-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5-oxopentyl)cyclohexanone bis ethylene ketal A mixture of 520 mg. (0.902 mmole~ of trans-3-~2~
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(5-oxopent-2-enyl)cyclohexanone bis ethylene ketal and 100 mg. of 5% Pd/C/50~ water in 15 ml. of ethanol was stirred under cne a~mosphere of hydrogen gas until one equivalent of hydrogen was absorbed. The reaction was filtered through l.0 diatom~ceous earth and evaporated to give a quantitative yield of thé title compound as an oil.
P~R ~cDsl 0.80 (m, terminal methyl), 1.32 (s, gem dimethyl), 3.9 (m~ ethylenes), 4.78 (m, dioxolane methine), 5.08 ~s, benzylic methylene), 6.85 (m, ArH), 7.08 (d, 3=8Hz, ArH) and 7.42 (m, PhH).
Deketalization according to the procedure of Example
8 afords the corresponding (5-oxopentyl)cycloalkanone as an oil.
PMR ~CDCl 0.82 (m, terminal methyl), 1.23 ~s, gem ~0 dimethyl), 5.06 ~s, benzylic methylene~,.6.88 (m, ArH), 7.03 ~d, J=8Hz, ArH), 7.36 (bs, PhH) and 9.58 (t, J=2Hz, CHO).
The remaining products of Example 10 are reduced and deketalized in like manner to the corresponding 5 oxopentyl ketones.
n~
~4 -Trans-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-~-(2-hydro~ypropyl)cyclohexanone ethylene ket~l Diastereomers A and B
To a 0 C~ solution of 1-72 ml. t5.00 mmole) of me~hyl magnesium iodide (2.9M in 5 ml. of ether) was added a solution of ~.O g. (4.06 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~-4 (2-oxoethyl)-cyclohex~none ethylene ketal in 5 ml. of ether. The reaction was stirred 30 minutes and then added to 250 ml.
saturated ammonium chloride and 250 ml. ether. The organic extract was washed with 2S0 ml. of saturated sodium chloride, dried over magnesium sulfate and evapo-rated to an oil. The crude oil was puri~ied via high pressure liquid chromatogra~hy on four 60 cm x 9.5 mm Porasil B (a form of silica gel available from Waters Associates, Milford~ Mass., U~SoA~ ) columns eluted with 60% ether-hexane to yield in order of elution 746 mg.
(36%~ of diastereomer A of the title compound and 935 mg.
~0 (45%) ~f diastereomer B of the title compound.
Diastereomer A:
IR (CHC13) 3571, 3472, 1613 and 1575 cm 1 MS (m/e) 508 (M~).
P~R ~TcMsl 0.85 (m, sidechain methyl), 1.06 (d, J=6Hz, methyl), 1.26 (s, gem dimethyl), 3.0 (m, benzylic methine), 3.7 (m, carbinol methine), 3.98 (s, ethylene), S.02 (s, benzylic methylene), 6.81 (d, J=2Hz, Ar~I), 6.81 (dd, J=8 and 2Hz, ArH), 7008 (d, J=8~1z, ArH) and 7.37 (m, PhH). 0 Diastereomer B:
IR (CHC13) 3610, 3460, 1618 and 1575 cm 1 MS (m/e) 508 (M ).
CDC13 0.85 ~m, sidechain methyl), 0 99 (d J 6H
meth~l), 1.27 (s, gem dimethyl), 3.1 (m, benzylic methine), 3.55 ~m, carbinol methine), 6.82 (m, Ar~), 7.04 (d, J=8Hz, ArH) and 7.35 (m, PhH).
-E~AMPLE 14 .
Cis-3- [ 2~benzyloxy-4-(1,1-dimethylheptyl)phenyl]
trans-4-(2-propenyl)cycloheptyl d-mandelate Diastereomer A & B
. . _ _ ~
A mixture of 2.2 g. (4.7~ mmole) of Cls-3-[2-benzylo~y-4-(1,1-dimethylheptyl)phenyl]-trans=4-(2-propenyl)cycloheptanol, 869 mg. (5.72 mmole) of d-mandelic acid and 110 mg. (0.579 mmole) of p-toluenesulfonic acid monohydrate in 40 ml. of benzene was heated at reflux for 7 hours. Water was removed via a soxhlet extractor ~illed with a synthetic crystalline aluminosilicate (moLecular sieve) such as those distributed by the Linde Company or the Davison Chemical Company. The reaction was stirred at 25 C. for 9 hours and then added to 300 ml.
of satuxated sodium bicarbonate and 300 ml~ ether. The e~her phase was separated and washed once with 300 ml~
of saturated sodium bicarbonate, dried over ~agnesium sulfate and evapsrated (aspirator) to an oil. The crude oil was purified via column chrvmatography on silica gel eluted with 15~ ~ther-hexane to yield in order o~ elution 1.08 g. t38~) o~ diastereomer A of the ~itle compound, 0.233 g. (8~) of mixture and 1.12 g. of diastereomer B
of the title compound as an oil~
Diastereomer A:
~ . _. ._ m.p.: 86-90 C. (Methanol) ~RMS (m/e) 596.3883 (M~, calc'd. for C40H520~:
596.3852), 444, 359, 354, 313, 269 and 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimet~yl), 2.90 (m, benzylic methine), 3.45 (m, ester methine), 4.5-6.0 (m, olefinic and mandelate ~), 5.06 (s, benzyl ether methylene), 6.90 (m, ArH) and 7.38 (m, PhH).
I~]CH3O~, 25C. ~4 42 4 n ~
Diastereomer B:
HRMS (m/e) 596.3855 (M , calc'd. for C40HS204:
596.3852), 354, Z6g, 107 and 91.
PMR ~cMSl 0.82 (m, terminal methyl), 1.21 (s, gem dimethyi), 2.80 (m, benzylic methine), 3.40 (m, ester methine), 4.5-6.0 (m, olefinic and mandelate H), 6.80 tm. Ar~) and 7.25 (m, PhH).
~]CH30H, 25C- = +S3 34 n 4 -6~-Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)cycloheptanol Enantiomer A
A mixture of 1.25 g. (2.09 mmole) of cls-3-12-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)cycloheptyl d-mandelate, diastereomer A, and 577 mg. (4.18 mmole) of potassium carbonate in 20 ml.
methanol, 5 ml. tetrahydrofuran and 2 ml. of water was stirred at 25 C. for 20 hours. The reaction was added to 300 ml. water-250 ml. ether. The ether extract was washed once with 300 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 75 g~ of silica gel eluted with 33~ ether-hexane to yield 650 mg. (67%) of the title compound as an oil HRMS (m/e) 462.3482 (M , calc'd. ror C32H46~2-462.3490) r 377, 313, 269, 233, 227 and 91.
[ ]CH30H, 25 C. = 20.18 In like manner 1.25 g. (2.09 mmole) of cis-3- [2-kenzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-t2-pro-penyl)cycloheptyl d-mandelate, diastereomer ~, was converted to 383 mg. (40~) of c s-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-pxopenyl)cycloheptanol enantiomer B as an oil .
HRMS (m~e) 462.3543 (M , calc'd. for C32H4602:
462.3490), 377, 313, 269, 233, 227 and 91.
[ lCH30H~ 25 C. = ~16.06 4 ~ ~
EY~ PLE 16 Cis-3-[2-Hydroxy-4-~1,1-dimethylheptyl)phenyl]-trans~4-(2-aminoethyl)cyclohexanol hydrochloride _ A mixture of 1.00 gO (Z~77 mmole) of cis-3- [2-hydroxy-4-(1,1-dimethylheptyl~phenyl]-tra~s-4-(2-oxo-eth~L)cyclohexanol, 2.31 g. (30.0 mmole) of ammonium acetate and 177 mg. (2.77 mmole) of sodium cyanoboro-hydride in 10 ml. of methanol was stixred for 16 hours at 25 C. The pH of the reaction was made <2 with con-centrated hydrochloric acid and the methanol evaporatedon a rotovapor. The residue was dissolved in 200 ml.
of water and 20 ml. of methanol and the solution washed twice with 200 ml. of ether. The aqueous phase was separated and made basic (pH>10) with conce~trated sodium hydroxide, saturated with sodium chloride and extracted with 200 ml. ~ ether. This ether phase was removed, dried over magnesium sulfate and evaporated (aspirator) to an oil. The oil was dissolved in dichloromethane and excess ethereal hydrogen chloride added forming an oily precipitate which crys~allized from ether-ethyl acetate-ethanol (1-1-13 solution upon cooiing to yield 136 mg. (12%) of the title compound.
m.p.: 218-220 C. (etherr ethyl acetate, ethanol) H~MS (m/e) 361~2993 (M~, calc'd. for C23H39N02:
361.2971)~ 276, 259 and 241.
3 ~
Cis-3-[2-Benzyloxy~4-(l,l~dimethylheptyl)phenyl]~
~ trans-4-oxomethylcyclohexanol A mixture of 14.4 g. (29.9 mmole) of c~s-3-[2-benzyloxy-4~ dimethylheptyl)phenyl]-trans-4 di-methoxymethylcyclohexanol, 150 ml. of 1,4-dioxane and 150 ml. of 2N hydrochloric acid was refluxed for one hour~ The reaction was cooled and added to 2 liters of saturated sodium chloride. The aqueous quench was ex-tracted twice with 300 ml. of ether and the combined ether extract washed once with saturated sodium bicar-bona-te, dried over magnesium sulfate and evaporated on a rotovac to give a quantitative yield o~ the title compound as an oil.
IR (CHC13) 3546, 3401, 1715, 1607 and 1572 cm 1 MS (m/e) 436 (M ), 352, 345, 328, 310, 299, 259 and 91 .
P~R ~CDCl 0.82 (m, terminaL methyl), 1.22 ~s~ gem dimethyl), 2.75 (m, benzylic methine), 3.65 (m, carbinol methine), 5.01 (s, benzylic methylene), 6.83 (mr ArH), 7.06 ~d, J=8Hz, ~rH) and 7.36 (s, PhH).
Similarly, 6.3 g. (13.07 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)p}lenyl]-cis-4-dimethoxy-methylcyclohexanol (contains some of the ClS-3, trans-4 isomer) was converted to 2.05 g. (36~) of rans-3-[2-benzyloxy-4-~ -dimethylheptyl)phenyl]-clS- 4-oxomethyl-cyclohexanol and 2~2 g. (39~) of the ClS-3~ trans-4 isomer.
Separation was achieved via column chromatography on 120 g. oE silica gel eluted with 66~ ether-hexane.
Trans, cis isomer:
IR (C~C13) 1715, 1607 and 1557 cm 1.
MS ~m/e) 436 (M ), 418, 351 328 and 91.
CDC13 0.86 (m, ~erminal methyl), 1 28 (s g dimethyl), 2.7 (m, benzylic methine), 4.22 (m, carbinol methine), 5.13 (s, benzylic methylene), 6.9 (m, ArH), 7~15 ~d, J=8Hz, ArH), 7.42 (bs, PhH) and 9.42 (d, J=3Hz, C~O).
~ ~ 8 ~
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-oxomethylcyclohexanol oxime A mixture of 1.5 g. (3.44 mmole) of cis-3- r2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans--4-oxo-methylcyclohexanol and 358 mg. (5O15 mmole) of hydroxyl-amine hydrochloride in 10 ml. of pyridine was stirred at 25 C. for 24 hours. The reaction was added to one liter of 10~ hydrochloric acid and extracted with 250 ml.
ether. The ether extract was washed with 200 ml. satura~ed sodium bicarbonate, 200 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 1~40 g. (90%) of the title compound as an oil.
IR (CHC13) 3533, 3300, 1612 and 1572 cm 1.
MS (m/e) 451 (M+), 433 and 91.
PMR ~cMSl 0.86 (m~ te~minal methyl), 1.28 (s/ ~em dimethyl), 2.5-4.0 (m, 3H), 5~08 (s, banzylic methylene), 6.39 (m, lH), 6.7-7.2 (m, ArH) and 7.40 (s, PhH).
In like manner trans 3-[2 benzyloxy-4-(1,1-dimethyl-heptyl)phenyl] -cis-4 oxomethylcyclohexanol oxime was prepared in 89% (1.84 gO) yield as an oil from 2.00 g.
l4.59 mmole) o~ trans-3-[2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-cis 4-oxomethylcyclohexanol.
IR (CHC13) 3497, 3225, 1600 and 1562 cm 1.
~5 MS (m/e) 451 (M~), 433, 416, 362, 348 ~nd 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 4.13 (m, carbinol methine), 5~08 (s, benzylic methylene), 6.85 (m, ArH), 7.08 (d, ~--8Hz, ArH) and 7.40 (bs, PhH).
3 ~
~XAMPLE 19 Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-rans-4-(2-carbomethoxyethenyl)cyclohexanol . ~
To a 25 C. slurry of 242 mg. (10,1 mmole) of 5 sodium hydride in 20 ml. tetrahydrofuran and 10 ml.
dimethylf~rmamide was added dropwise a solution of 1.83 g.
(10 mmole) of methyl dimethylphosphonoacetate in 5 ml.
of tetrahydrofuranO The reaction was stirred 5 minutes and then a solution of 2.0 g. (4.58 mmole) of cis-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-oxomethylcyclohexanol in 5 ml. of tetrahydrofuran was added dropwise~ The reaction was stirred 15 minutes Longer and then added to 700 ml. of saturated sodium chloride. The quenched reaction was extracted with 250 ml.
o~ ether, the extract dried over magnesium sulfat~ and evaporated to an oil. The crude oil was- purified via column chromatography on 50 g. of silica gel eluted with 50~ ether-pentane to yield 1.28 g. (58%) of the title compound as an oil.
IR ~CHC13) 3389, 1709, 1650, 1610 and 1557 cm 1.
MS (m/e) 492 (M~, 407, 383, 323 and 91.
PMR ~cMcl 0.83 (m, terminal methyl), 1.25 (s, gem dimeth~l), 3~10 (m, be~zylic methine) 3.62 (s, methyl ester~, 3.62 (m, carbinol methi.ne), 5.05 (s`, benzylic meth~lene), 5.57 (d, J=16Hz, olefinic H), 6.85 (m, ArH), 7.05 (d, J=8Hz, ArH) and 7.40 (s, PhH).
_-73~
~XAMPLE 20 Cis-3-[2-Benzyloxy-4-~1,1-dimethylheptyl)phenyl]-trans-4-(2-carbamoylethenyl)cyclohexanol A mixture of 3.0 g. (6.88 mmole) of cis-3- [2-benzyloxy-4-tl,l-dimethylheptyl)phenyl~-trans-4-oxo-methylcyclohexanol and 2.43 g. (7.58 mmole) of carbæmoyl-methylenetriphenylphosphorane in 40 ml. of dichloromethane was heated at reflux for 24 hours. The reaction was concentrated and ether added to cause crystallization of triphenyLphosphine oxide. The residue was purified ~irst via column chromatography on 120 g. of silica gel eluted with ether and ~hen on 111 g. o~ neutral alumina eluted with 0-100% ethyl acetate-ether to yield 2~0 g. ~61%) of the title compound as an oil.
IR (C~C13) 3533, 1678, 1612 and 1587 cm 1 MS (m/e) 477 (M ), 460, 386, 368 and 307.
PMR ~cM~l 0.84 (m, termi~al methyl), 1.22 (s, gem dimethyl~, 3.05 (m, benzylic m~thine), 3.70 (mr carbinol methine), 5.08 (s, benzylic methylene), 5.50 (d, J=16Hæ, olefinic), 6.95 (m, ArH), 7.07 (d, J=8Hz, ArH) and 7.42 (bs, PhH).
Cis 3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-~-l2-carbomethoxyethyl~cyclohexanol A mixture of 1.28 g. (2.60 mmole) of ClS-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4 (2 carbomethoxyethenyl)cyclohexanol and 640 mg~ of 5~
Pd/C/50% H2O in 20 ml. of methanol was s~irred under one atmosphere of hydrogen for 75 minutes. The reaction was filtered through diatomaceous earth and the filtrate evapoxated. The residue was again mixed with 640 mg.
of fresh 5~ Pd/C/50~ H2O in 20 ml. of methanol and stirred under one atmosphere of hydrogen for 30 minutes, then filtered and evaporated as before. The residual oil was crystallized in ether-pentane to yield 540 mg. (51%) of the ti~le compound.
m.p.: 81-83 C. (ether-pentane) IR (CHC13~ 3521, 3289, 17Z4, 1612 and 1574 cm 1.
MS (m/e) 40~ (M+), 386, 355, 332 and 319.
PMR ~cMSl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 2.65 (m, benzylic methine), 3.46 (s, methyl ester), 3.~ (m, carbinol methine), 5.7 (broad, OH), 6.75 (m, ArH) and 7.03 (d, J=8Hz, ArH).
AnalYsis: Calc'd. for C H O :
C, 74.22; H~ 9.97.
Found: C, 73.85; H, 9.64.
Similarly, cis-3 ~2 phenyl]-trans-4-(2-carbamoylethyl)cyclohexanol was pre-.
pared in 39% (630 mg.) yield from 2.00 g. (4.19 mmole) o c -3 [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]- 0 trans-~-(2-carbamoylethenyl)cyclohexanol.
m~p.: 152-153 C. (ethyl acetate) IR (KBr) 3267, 3095, 1661, 1618 and 1575 cm 1.
MS (m/e) 389 (M ), 372, 371, 354, 353, 286, 287 and 269.
4 0 ~
PMR ~CDC13 ~ Dç-DMSO)~ 0.83 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.0 (m, benzylic methine), 3.70 (m, carbinol methine), 6.75 (m, ArH) and 7.03 ~d, J=8Hæ, AxH).
Analysis: Calcld. for C24H39NO3:
C, 73.99; H, 10.09; N, 3.60.
~ound: C, 74.10; H, 10.11; N, 3.52.
EX~MPLE 22 Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phen~l]-trans-4-(2-carboxyethyl)cyclohexanol A mixture of 1.01 gO (2.50 mmole) of cis-3-[2-hydroxy-4~(1,1-dimethylheptyl)phenyl]~trans-4-(2-carbomethoxyethyl)cyclohexanol, 25 ml. 6N sodium hydroxide and 25 ml. dioxane was heated at reflux for 40 minu~es and then cooled to 0 C~ and acidiied with 6N hydro-chloric acid. The quenched reaction was diluted with saturated sodium chloride and e~tracted several times with ether and then dichloromethane. The combined organi ex~ract wa~ evaporated and the residue recrystallized from ethyl acetate to yield 314 mg. (32%~ of the title comFound .
m.p.: 194-195 C. (ethyl acetate) IR (KBr) 3367, 3125, 1694, 1612 and 1575 cm 1.
HRMS (m/e) 390.2758 (M , calc'd. for C~H3804:
390.~760), 305, 287, 26g.
PMR (CDC13, D6-DMSO) ~TMS 0.~2 (m, terminal methyl), 1.~3 ~s, gem dimethyl), 3.50 (m, carbinol methine), 6.78 . (m, ArH) and 7.04 (d, J-8~z, AxH)~
~i7~
Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl~-trans-~ (3-aminopropyl)cyclohexanol To a 0 C. slurry of 500 mg. (13.1 mmole) of lithium S al~ninum hydride in 15 ml. of tetrahydrofuran was added a solution of 460 mg. (1.18 mmole) of cis-3-[2-hydroxy-4-(1,1-dimethylheptyl~phenyl3-trans-4-(2-carbamoylethyl~-cyclohexanol in 14 ml. of tetrahydrofuxan. The reaction was stirred at 25 C. for one hour and at re1ux Eor 20 hours. The reaction was cooled to 0 C. and quenched by the addition of a 30% solution of sodium potassium ~artrate. The quenched reaction was extracted with ethyl acetate, the extract dried over magnesium sulfate and evaporated to an oil. Crystallization of the residue in ether-ethyl acetate gave 390 mg. (88%) of the title compound.
m.p.: 137-138 C.
MS (mJe) 375 (M ), 358 and 34Q.
PMR ~CDC13 ~ D6DMSO)~TMS 0.80 (m, te~ninal methyl~, 1~22 (s, gem dimethyl), 3.34 (bs, exchangeable OH), 3.75 (m, car~inol methine), 6~75 (m, ArEI) and 7.00 (d, J=8Hz, ArH)~
The following compounds were similarly prepared:
CiS-3- ~2-hydroxy-4-(1,1-dimethylheptyl)phenyl~-tr ns-4 ~iAonetAvlcyclohex~nol in 43% (819 mg.) yield rom 1.99 g. ~5.51 mmole) of cis-3~~2 hydroxy-4-(1,1-dimethylheptyl)phenyl]-_rans-4-oxomethylcyclohexanol o~ime~
m~p.: 104-106 C. (ethyl acetate-pentane) IR (KBr) 3205, 1602 and 1572 cm 1.
HRMS (m/e) 347.2853 (M , calc'd. for C22H37NO2:
347.2815), 245, 227.
4 l~ ~
trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]~
cis-4-aminomethylcyclohexanol in 44% (427 mg.) yield . . __~
from 1~01 gO (2.80 mmole) of trans-3-[2-hydroxy-4-(l,1-dimethylheptyl)phenyl]-cis-4-oxomethylcyclohexanol oxi~e~
m.p.: 121-124 C. (ether-hexane) MS (m~e) 347 (M~), 330, 312, 245 and 227.
Cis-3 [2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-dimethylaminopropyl)cyclohexanol hydrochloride A mixture of 340 mg. ~0.906 mmole) of cis-3-~2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-amino-propyl)cyclohexanol, 268 ~1. of 37~ formaldehyde and 137 ~1. of formic acid was heated at 100 CO for 30 minutes. The reaction was cooled and added to ether and saturated sodium bicarbonate. The ether extract was dried over magnesium sulfate and evaporated to yield an oiL which was purified via column chromatography on 8 ~. of silica gel eluted with 50~ methanol-dichloro-methane to yield 78 mg. (21%~ of the free base of the title compound as a glass.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s gem dimethyl), 2.19 (s, N-methyls), 3.7 (m, carbinol methine), 5.55 (broad, O~), 6.75 (m, ArH) and 6.98 (d, J=~H2, ArH).
HRMS (m/e) 403.3447 (M , 100%, calc'd. for C26H45NO2:
403.3439).
The above fxee base was dissolved in ether-ethanol and excess ethereal hydrogen chloride added. The solution was then evaporated a~d the residue crystallized from ether-dichloromethane to yield 71.8 mg. (18%) of the title compound.
m.p.: 170-175 ~. (ether-dichlo~omethane) The ~ollowing compounds were prepared by the above pxocedure:
CiS- 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-. .
~rans-4-N,N-dimethylaminomethylcyclohexanol hydrochloride .
in 25~ (30mg.) yield from 100 mg. (0.288 mmole) o CiS-3 ~ 2-hydroxy-4-(1,1-dimethylheptyl)phenyl]~trans-4-aminomethylcyclohexanol.
m.p.: 202-203 C. (ether-dichloromethane) MS (m/e) 375 (~ ) 3 ~
Free Base:
PMR (CDC13)~ 0~82 (m, terminal methyl), 1.30 (s, gem dimethyl), 2.28 ~s, N,N-dimethyl), 3.75 (m, carbinol methine), 6.9 (m, ArH) and 7.12 (d, J=8Hz, ArH).
HRMS (m/e) 375.3140 (M , calc'd. for C24H41N02:
375 . 31271 -rans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-. .. r~
cis-4-N,N-dimethylaminomethylcyclohexanol hydrochloride .. .. _ ... . .. .....
in 25~ ~198 mg.) yield from 672 mg. (1.94 mmole) of trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl] -ClS-4-aminomethylcyclohe~canol.
m.p.: 176-178 C.
3) CDC13 0.82 (m, terminal methyl), 1 25 (m, gem dimethyl and methylenes), 4.26 (m, carbinol methine) and 5O6-7~2 (m, ArH~.
Free Base: -IR (C~C13) 3333, 1607 and 1563 cm 1.
MS (m/e) 375 ~M ), 330 and 245.
~ - , EXAMPLE :2 5 _ _ Trans-1-[2-~ydroxy-4-(1,1-dimethylheptyl)~henyl]-2-~(3-hydroxypropyl)cyclohexane A mixture of 1.9 g. (5.08 mmoles) of trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-2-(3-hydroxypropyl)-cyclohexanone and 10.2 ml. of hydrazine hydrate ln 20 ml.
of ethylene glycol is heated at 100 C. for an hour.
Th~ reaction was cooled to 60 Cu and 4.05 g. (72.3 m~oles) of solid potassium hydroxide added. The resultant mixture was heated for 2 hours at 200 C., then cooled and added to 500 ml. lN hydrochloric acid and 300 ml. ether. The ether extract was washed with 300 ml. saturated sodium chloride, 300 ml. saturated sodium bicarkonate, dried over magnesium sulfate and evaporated under reduced pressure lS ~aspirator) to an oil. The crude oil was purified via column chromatography on 100 gO of silica gel eluted with 70~ ether-hexane to yield 406 mg. (22~) of the title compound as a~ oil.
IR (C~C13) 3509r 3279, 1605, 1595 and 1570 cm 1.
MS (m/e) 3~0 (M+), 345, 342, 275~ 257, 233, 215, 147 and 141.
P~R ~cMcl 0.82 (m, terminal methyl), 1.25 (s, gem dimet~yl), 2,58 (m, benzylic methine), 3.46 (bt, J=6Hz, hydroxy methylene), Su0 (broad, OH), 6.67 (d, J-2Hz, ArH), 6.79 (d, J-8 and 2Hz) and 7.02 (d, J=8Hz, ArH).
4 ~3 ~
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(2-propenyl)~ enzyloxycyclohexane . . _ . . . _ To a slurry of 214 mg. (8.92 mmole) of sodium hydride in 10 ml. dimethylformamide was added a solution of 2.0 g. (4.46 mmole) of cis-3-[2-benzyloxy-4-(1,1-di-methylheptyl)phenyl]-trans-4-(2-propenyl~cyclohexanol in 10 ml. of dimethylformamide. The reaction was stirred 5 hours and then 0.6 ml. (4.9 mmole) of benzyi bromide was added. The reaction mixture was stirred 18 hours longer and added to S00 ml. saturated sodium chloride and 500 ml. ether. The organic extract was dried o~er magnesi~ sulfate and evaporated to yield an oil which was purified via column chromatography on 100 g. of silica gel eluted with 5~ ether-hexane to yield 2.0 g (83~) of the ti~le compound as an oil.
IR (C~C13) 1639, 1600 and 1567 cm 1.
HRMS (m/e) 538.3823 tM+, calc'd. for C38H5002:
538.3798), 453, 299~ 255 and 91.
PMR ~CMCl 0.83 (m, terminal methyl), 1.24 (s, gem dimethyl), 2.85 and 3.40 (m, ether methines), 4.50 and 5.05 (s, benzylic methylenes), 4.6-5.0 and 5.2-6.1 (n, ~inyl H), 6.9 (m, ArH), 7.28 and 7.34 (bs, Ph~I).
0 ~
-8~-Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-trans-4-(3-methoxypropyl)cyclohexanol To a slurry of 172 mg. (7 mmole) of sodium hydride in lS ml. di~ethylformamide was added 2.0 g. (3.60 mmole) of CiS~3- ~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans~4-(3-hydroxypropyl)-1-benzyloxycyclohexane in lS ml.
-dimethylformamideO The reaction mixture was then heatedat 40-50 C. for 3 hours, then cooled to 25 C. and 0.663 ml. (7.0 mmole) of dimethylsulfate was added. The res~ltant mixture was stirred 18 hours at 0 C. and then ~dded to 250 ml~ saturated sodium chloride and 250 ml.
ether. The organic extract was dried over magnesium sulfate and evaporated to an oil. The crude oil was puri.~ied via colum~ chromatography on 75 g. of silica gel eluted with 20~ ether-hexane to yield 500 mg~ (24%~
of cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-tr.ans-4-(3-methoxypropyl)cyclohexanol as an oil.
PMR ~CDCl 0.83 (m, terminal methyl), 1.23 ~s, gem dimethyl), 3.20 (s, OCH3), 2~6-4.0 (m), 4.54 and 5.06 (s, benæylic methylenes~, 6.85 (m, ArH) and 7.23 (m, PhH).
Debenzylation of 500 mg. (0.874 mmole) of the pxoduct according to the procedure of Example 6 gives the title compound.
m.p.: 72-74 CO (pentane) MS (m~e) 390.3100 (M~, calc'd. for C25H42O3; 390.3123), 372, 286, 272 and 147~
PMR (CDC13) ~ 0.85 (m), 1.22 (sr gem dimethyl), 3.20 tocH3)~ 2.4-~.2 (several m), 5.05 (bs, OH), 6.8 (m, ArH) and 7.02 (d, J=8Hz, ArH).
o ~
-8~
EX~MPLE 28 Trans-3-[2-Benzyloxy-4-(R)-tl-methyl-4-phenylbutoxy)-_ phenyl]~4-~2-propenyl)cycloheptanone Using the procedure of Example 1, 23 g. (54.1 mmole) of (R~~l-hromo-2-benzyloxy-4 (l~methyl-4-phenylbutoxy)-benzene and 7.5 g. (50.0 mmole) of 4-(2-propenyl)-2-cyclohepten-l-one gave 8.14 g. ~306) o~ the title compound as an oil.
,~o [~]D = -10.61 (C = 1.077, CHC13) HRMS (m/e) 49602964 (~+, calc'd. for C34H4003:
496.2967), 405, 259, 241 and 91.
CDC13 1.22 (d, J=6~z, methyl), 4.33 (m side chain me~hine~, 4.6-5.0 and 5.2-6.0 (m, vinyl H), 5.00 (5, benzylic methylene), 6.45 (m, ArH), 7.00 (d, J=8H2, ArH), 7.24 ~s, PhH) and 7.42 (s, PhH~.
Cis-3-[2-Benzylo~y~4-(R)-(l-methyl-4-phenylbutoxy)pllenyl]-4-trans-(2-propenyl)cycloheptanol and Isomeric Alcohol . .
Using the procedure of Example 2, 8.14 g. (16.5 mmole) of trans-3-[2-benzyloxy-4-~R) (l-methyl-4-phenylbutoxy)-phenyll 4-(2-propenyl)cycloheptanone gives in order of elution 3.14 g. (39%) of the trans-3, CiS-4 isomer and 3.23 g. ~40~) o~ the title compound.
. Trans-3_2C50is 4 Isomero la]D = -10.40 (C = 1.058, CHC13) IR ~CHC13) 3508, 3448, 1626 and 1600 cm 1 HRMS (mJe) 498.3120 (M~, calc'd. for C34H4203:
~98v3123) and 91.
PMR ~cDsl 1.22 (d, J-6Hz, methyl), 2.6 (m, benzylic methylene), 3.2 (m, benzylic methine), 4.0 (m, carbinol methine), 4.25 (m, sidechain methine), 4.6~5.0 and 5.2-6.0 (m, ~inyl H), 5.02 (s, ben~ylic methylene), 6.4 (m, ArH), 7.20 and 7.38 (s, PhH).
Cis-3, Trans-4 Isomer:
~ ~25 = _g 97o (C = 1.471, CHC13) ~ R (CHC13) 3508, 3448, 1626 and 1600 cm 1.
HRMS (mje) 498.310a (M~, calc'd. for C34H~203:
498.3123), 261, 243 and 91.
PMR ~TMSl 1~22 (dl J=6Hz, methyl), 2.55 (m, benzylic 2S methylene and methine), 3.65 (m, carbinol methine~, 4.20 ~m, sidechain methine), 4.6-5.0 and 5.2-6.0 (m, vinyl ~), 5.02 (s, ben2ylic methylene), 6.4 (m, ArH), 7.00 (d, J=8Hz, ArH), 7.2 and 7.38 (s, PhH).
4 ~ ~
--~6--EX~lPLE 3 0 Cis-3-~Z-Benzyloxy 4-(R)-(l~methyl-4-phenylbutoxy)-phenyl3-4-trans-( 3 -hydroxypropyl)cycloheptanol Using the proc~dure of Example S, 1.03 g. (2.07 mmole) of CiS~3- [2-benzyloxy-4-(R)-(l-methyl-4~phenyl-butoxy)phenyl]-4-trans-(2-propenyl)cycloheptanol gave 1.0?3 g~ (100%) of the title compound as an oil.
[ 125 = _g ~3O (C = 1.051, CHC13) IR (CHC13) 3571, 3389, 1600 and 1S74 cm 1.
10HRMS (m/e) 516.3216 ~M~, calc'd. for C34H44O4:
51~.3228~.
PMR ~TMcl 1.22 (d, J=6~z, methyl), 2.7 (m, ben2ylic methylene), 3.42 (bt, C~2OH), 3.85 (m, carbinol methine), 4.35 (m, sidechain methine), 5.00 (s, benzylic methylene), lS 6.45 (m, ArH), 7.02 (d, J=8Hz, ArH), 7.25 and 7.42 (s, PhH), 4 ~ fl ~7 Cis-3-[2-Hydroxy-4-(R)~ methyl 4-ph~nylbutoxy3-phenyl~-4-tr2ns-(3-hydroxypropyl)cycloheptanol ~ ~ . . .
Using the procedure of Example 6, 1.O g. (1. 93 mmol2) 5 of CiS-3- [2-~enzyloxy-4-(R)-(l-methyl~4-phenylbutoxy)~
phenyl~-4-trans-(3-hydroxypropyl)cycloheptanol gave 500 mg. (61%) of the title compound as an oil.
[a]25 = _7.53o 5C = 0.68, CHC13) IR ~CHC13) 3508, 3333, 1600 and 1587 cm 1.
HRMS (m/e) 426.2758 (M , calc'd. for C27X3804:
426.~760~, 280, 262, 123 and 91~
PMR ~TMSl 1.22 (d, J=6Hz, methyl), 2.58 (m, benzylic methylene), 3.40 ~t, J=7Hz, CH2OH), 3.8 (m, carbinol methine), 4.15 (m, sidechain methine), 6.35 (m, ArH), 6~95 (d, J=8Hz, ArH) and 7.19 (s, PhH).
o ~
-~8-EXAMPLE 3_ Cis-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4.-(2-propenyl)-1-phthalimidocyc.loheptane To a 25 C. mixture ~f 1.00 g. (2.16 mmole) o~
trans-3-[2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl] -CiS-4-(2-propenyl)cycloheptanol, 476 mg. (3.24 ~nole) o phthalimide and 846 mgO (3.24 mmole) o~ triphenylphosphine in 1.0 ml. acetonitrile was slowly added 0.51 ml. (3.24 mmole) of diethyl azodicarboxylate. The reacticn mixture was stirred 5 hours and then dissolved in 250 ml. ether.
~rhe ether phase was washed once with 250 ml. water, once with 250 ml. saturated sodium chloride, dried over magne~ium suL~ate and evaporated to an oil. The crude oil was purified via column chromatography on 200 g. of silica gel eluted with 10~ ether hexane to yield 820 mg.
~64~) of the title compound as an oil.
IR (CHC13) 1761, 1695~ 1625, 1603 and lS63.
HRMS (m/e) 591~3799 (M , calc'd. for C40H49N03:
591.3700), 506, 353 and 91.
PMR ~CDCl 0.8 (m, terminal methyl), 1.20 (s, gem dimethyl), ~.98 (m, ben2ylic methine), 4.4 (bm, methine)~
4~5-5.0 (m, vinyl H), 5.03 (s, benzylic methylene), 5.2-6.0 (m, vinyl H), 6.78 (m, ArH), 7.02 (d, J=8Hz, ArH), .33 and 7.65 (m, ArH and PhH).
~ ~8~Q~14 Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenylJ-rans-4-(2-propenyl)-1-aminocycloheptane .
A solution of 1~0 g. (1.68 mmole) of cis-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]~~rans-4~(2-propenyl) l-phthalimidocycloheptane and 0.834 ml.
(1.68.mmole) of hydrazine hydrate in 2 ml. ethanol was heated at reflux for 20 minutes forming a precipi~ateO
The reaction was cooled, filtered and the solid washed with 200 ml. ether~ The filtrate was washed once with 100 ml. saturated sodium chloride, once with 100 ml.
50~ 2N sodium hydroxide, dried over magnesium sulfate and~evaporated to yield 770 mg. (99~) of the title compound as an oil.
IR tCHC13) 3125, 16g5, 1632~ 1600 and 1562 cm HRMS (m/e) 461.3607 (M , calc'd. for C32H~7NO:
461.3646), 420, 370, 354 and 91.
CDC13 0~8 (m, terminal methyl), 1 24 (s dimethyl)r 2.9 (m, 2H), 4.6-5O0 (m, vinyl H), 5.04 (s, benzylic methylen ), 5.2-6.1 (m, vinyl H), 6.85 (m, ArH), 7.07 (d, J-8Hz, ArH) and 7.4 (m, PhH).
Following the procedures of Example 32 and of this example, cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phen~l]-tr2ns-4-(2-propenyl)-l-aminocyclohexane is prepared from trans~3-~2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-cis-4-(2-propenyl)cyclohexanol.
~XAMPLE 34 Cis-3-[2-Benzylo~y-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)-1-acetamidocycloheptane A mlxture of 500 mg. (1.08 mmole) of cis-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2 propenyl)-l aminocyclohept~ne, 131 mg. (1.08 mmole) 4-N,N-dimethylaminopyxidine and 0.101 ml. (1.08 mmole) of acetic anhydride in 5 ml. dichloromethane was stirre~
for one hour. ~he reaction was added to 100 ml. ether and washed-twice with 100 ml. lN hydrochloric acid and twice with 100 ml. saturated sodium bicarbonate. The organic phase was dried over magnesiwm sulfate and ~vaporated to give 485 mg~ (89~) of the title compound as an oil.
IR (CHC13~ 3389, 1652, 1602 and 1562 cm 1.
HRMS (m/e~ 503.3793 (M , calc'd. for C34H49NO2:
503.3751), 418, 412, 353 and 91.
PMR ~CDCl 0.82 (mr terminal methyl), 1~22 ~s, gem dimethyl), 1.86 (s, COCH3~, 2.95 ~m, benzylic methine)~
4~02 (bm, CHN), 4.6-5.0 (m, vinyl H), 5.08 (s, benzylic methylene), 5.3-6.0 (m, vinyl H), 6.85 (m, ArH), 7.03 (d, ~-8H~, ArH) and 7.38 (m, ArH)~
o ~
-Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-1-acetamidocycloheptane Using the procedure of E~ample 5, 1.7 g. (3.37 mmole) of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)-1-acetamidocycloheptane ga~e 962 mg.
(55~) of the title compound as an oil.
IR (CHC13) 3~48, 1652, 1600 and 1562 cm 1.
HRMS (m/e) 521.3813 (M , calc'd. for C34HSlNO3:
521.3856), 430, 371 and 91.
PMR CcDcl3 0.8 (mr terminal methyl), 1 20 (s gem dimethyl), ~85 (m, benzylic methine), 3.35 (m, CH2OH), 4.0 ~m, CHN)~ 5.05 (sl benzylic methylene), 5.38 (bd, NH), 6.8 (m, ArH), 7.00 (d, J=8Hz, ArH) and 7.39 (bs, PhH).
Cis-3-t4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-trans-4~(3-hydroxypropyl)-1-acetamidocycloheptane Using the procedure of Exampla 6, 960 mg. (1.84 mmole) ~0 of c iS- 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]~
tran~ -(3-hydroxypropyl)-1-acetamidocycloheptane gave 630 mg. (79%) of the title compound as an oil.
IR (CHC13) 3649, 3389l 3279, 1652, 1600 and 1562 cm 1.
HRMS (m/e) 431.3420 (M+, calc'd~ for C27H45N03:
~31.3388), 346, 287, 257, 161, 147 and 133.
PMR ~C~Cl 0.8 (mr terminal methyl), 1.20 ~s, gem dimethyl), 1.85 (s, COCH3), 2.82 (m, benzylic methine), 3.~2 (m, CH~OH), 4.0 (m, CHN), 5.6 (bd, NH), 6.75 (m, ArH) and 6.98 (d, J~8Hz, ArH).
By means of the procedures of Examples 34~ 35 and this example, cis-3-[4-(1,1-dimethylheptyl)-2-hydroxy-phenyl]-trans-(3-hydroxypropyl)-1-acet~midocyclohexane is prepared from cis-3-[2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-trans-(2-propenyl)-1-aminocyclohexane.
g) ~
Cis-3-[2-Benzyloxy-4-(1,1-dimethylhPptyl)phenyl]
trans-4-(3-hydroxypropyl)cyclohexanol bis-d-mandelate . . _ , .
A mix~ure of 31.3 g. (67.2 mmole) of CiS-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol, 25.5 g. (168 mmole) of d-mandelic acid and 1.0 g. (5.26 mmole) of p-toluene-sulfonic acid monohydrate in 500 ml. of benzene was heated at reflu~ for ll hours. Water was removed by 10 use of a sbxhlet extractor filled with 200 g. of 3A
molecular sieves. ~he reaction is cooled, added to one liter saturated sodium bicarbonate and extracted with four 500 ml. portions of ether. The combined organic extract was dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chroma-tography on 2 kg. of silica gel eluted with 40-50~ ether-hexane to yield in order of elution 18 g. (37%) of diastereomer A and 21 g~ (43~) of diastereomer B of the ti~le compound.
Diastereomer A
m~p.~ 112.5 C. (methanol) o L~]D = ~20.19 (C = 1.107, 5~ chloroform-methanol) PMR (CDC13)~ 0.84 (m, terminal methyl), 1.25 (s, gem dimethyl), 2.8 (m, benzylic methine), 3.45 (m), 4.0 (m), 4.6-5.2 (m), 5.05 (s, benæylic methylene), 6.88 (m, ArH), .27 and 7.34 (s, PhH).
_is: Calcld. for C H O :
~7 58 C, 76.81; ~I, 7.95.
Found: C, 76.49; H, 7.76.
__ In like manner, but using the same relative stoichiometric proportion of d-mandelic acid and p-toluenesulfonic acid monohydrate, 9.0 g. tl6 mmole) of cls-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-benzyloxypropyl~cyclohexanol gave, in order of elution, 4.1 g. (37%) of diastereomer A and 4.2 g. (38%) of diastereomer B of CiS- 3-[2-benzyloxy-4-(1,1)-dimethylheptyl)phenyl]-trans-4-(3-benzyloxypropyl)-d-mandeloyloxycyclohexane as solids.
Diastereomer A:
m.p.: 56-58 C.
[~]D5 = 0.292 (C = 1.25, C1130il) PMR ~CDCl 0.80 (m, terminal methyl~, 1.20 ~s, gem dimethyl), 2.9 ~m), 3.0-3.6 (m), 4.30 (s, benzylic methylene), 4.5-5.1 (m), 5.00 (s, benzylic methylene), 6.78 (m, ArH), 6.98 (d, J=8Hz, ArH), 7.17 (s, PhH) and 7.30 (s, PhH).
L0 D stereomer B:
.p.: 65-69 C.
[~]25 = ~40 95 (C 1 21 CH OH) PMR ~cDscl 0.80 (m, terminal methyl), 1.20 (s, gem dimethyl), 2.8 (m), 3.0-3.5 (m), 4.26 (s, benzylic methylene), 4.4-5.1 (m), 4.95 (s, benzylic methylene), 6.70 (m, ArH), 6.87 (d, J=8Hz), 7.12 (s, PhH) and 7.20 (s, PhH).
o ~
PMR ~CDCl 0.82 (m, terminal methyl), 1.23 ~s, gem ~0 dimethyl), 5.06 ~s, benzylic methylene~,.6.88 (m, ArH), 7.03 ~d, J=8Hz, ArH), 7.36 (bs, PhH) and 9.58 (t, J=2Hz, CHO).
The remaining products of Example 10 are reduced and deketalized in like manner to the corresponding 5 oxopentyl ketones.
n~
~4 -Trans-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-~-(2-hydro~ypropyl)cyclohexanone ethylene ket~l Diastereomers A and B
To a 0 C~ solution of 1-72 ml. t5.00 mmole) of me~hyl magnesium iodide (2.9M in 5 ml. of ether) was added a solution of ~.O g. (4.06 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~-4 (2-oxoethyl)-cyclohex~none ethylene ketal in 5 ml. of ether. The reaction was stirred 30 minutes and then added to 250 ml.
saturated ammonium chloride and 250 ml. ether. The organic extract was washed with 2S0 ml. of saturated sodium chloride, dried over magnesium sulfate and evapo-rated to an oil. The crude oil was puri~ied via high pressure liquid chromatogra~hy on four 60 cm x 9.5 mm Porasil B (a form of silica gel available from Waters Associates, Milford~ Mass., U~SoA~ ) columns eluted with 60% ether-hexane to yield in order of elution 746 mg.
(36%~ of diastereomer A of the title compound and 935 mg.
~0 (45%) ~f diastereomer B of the title compound.
Diastereomer A:
IR (CHC13) 3571, 3472, 1613 and 1575 cm 1 MS (m/e) 508 (M~).
P~R ~TcMsl 0.85 (m, sidechain methyl), 1.06 (d, J=6Hz, methyl), 1.26 (s, gem dimethyl), 3.0 (m, benzylic methine), 3.7 (m, carbinol methine), 3.98 (s, ethylene), S.02 (s, benzylic methylene), 6.81 (d, J=2Hz, Ar~I), 6.81 (dd, J=8 and 2Hz, ArH), 7008 (d, J=8~1z, ArH) and 7.37 (m, PhH). 0 Diastereomer B:
IR (CHC13) 3610, 3460, 1618 and 1575 cm 1 MS (m/e) 508 (M ).
CDC13 0.85 ~m, sidechain methyl), 0 99 (d J 6H
meth~l), 1.27 (s, gem dimethyl), 3.1 (m, benzylic methine), 3.55 ~m, carbinol methine), 6.82 (m, Ar~), 7.04 (d, J=8Hz, ArH) and 7.35 (m, PhH).
-E~AMPLE 14 .
Cis-3- [ 2~benzyloxy-4-(1,1-dimethylheptyl)phenyl]
trans-4-(2-propenyl)cycloheptyl d-mandelate Diastereomer A & B
. . _ _ ~
A mixture of 2.2 g. (4.7~ mmole) of Cls-3-[2-benzylo~y-4-(1,1-dimethylheptyl)phenyl]-trans=4-(2-propenyl)cycloheptanol, 869 mg. (5.72 mmole) of d-mandelic acid and 110 mg. (0.579 mmole) of p-toluenesulfonic acid monohydrate in 40 ml. of benzene was heated at reflux for 7 hours. Water was removed via a soxhlet extractor ~illed with a synthetic crystalline aluminosilicate (moLecular sieve) such as those distributed by the Linde Company or the Davison Chemical Company. The reaction was stirred at 25 C. for 9 hours and then added to 300 ml.
of satuxated sodium bicarbonate and 300 ml~ ether. The e~her phase was separated and washed once with 300 ml~
of saturated sodium bicarbonate, dried over ~agnesium sulfate and evapsrated (aspirator) to an oil. The crude oil was purified via column chrvmatography on silica gel eluted with 15~ ~ther-hexane to yield in order o~ elution 1.08 g. t38~) o~ diastereomer A of the ~itle compound, 0.233 g. (8~) of mixture and 1.12 g. of diastereomer B
of the title compound as an oil~
Diastereomer A:
~ . _. ._ m.p.: 86-90 C. (Methanol) ~RMS (m/e) 596.3883 (M~, calc'd. for C40H520~:
596.3852), 444, 359, 354, 313, 269 and 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimet~yl), 2.90 (m, benzylic methine), 3.45 (m, ester methine), 4.5-6.0 (m, olefinic and mandelate ~), 5.06 (s, benzyl ether methylene), 6.90 (m, ArH) and 7.38 (m, PhH).
I~]CH3O~, 25C. ~4 42 4 n ~
Diastereomer B:
HRMS (m/e) 596.3855 (M , calc'd. for C40HS204:
596.3852), 354, Z6g, 107 and 91.
PMR ~cMSl 0.82 (m, terminal methyl), 1.21 (s, gem dimethyi), 2.80 (m, benzylic methine), 3.40 (m, ester methine), 4.5-6.0 (m, olefinic and mandelate H), 6.80 tm. Ar~) and 7.25 (m, PhH).
~]CH30H, 25C- = +S3 34 n 4 -6~-Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)cycloheptanol Enantiomer A
A mixture of 1.25 g. (2.09 mmole) of cls-3-12-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)cycloheptyl d-mandelate, diastereomer A, and 577 mg. (4.18 mmole) of potassium carbonate in 20 ml.
methanol, 5 ml. tetrahydrofuran and 2 ml. of water was stirred at 25 C. for 20 hours. The reaction was added to 300 ml. water-250 ml. ether. The ether extract was washed once with 300 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 75 g~ of silica gel eluted with 33~ ether-hexane to yield 650 mg. (67%) of the title compound as an oil HRMS (m/e) 462.3482 (M , calc'd. ror C32H46~2-462.3490) r 377, 313, 269, 233, 227 and 91.
[ ]CH30H, 25 C. = 20.18 In like manner 1.25 g. (2.09 mmole) of cis-3- [2-kenzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-t2-pro-penyl)cycloheptyl d-mandelate, diastereomer ~, was converted to 383 mg. (40~) of c s-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-pxopenyl)cycloheptanol enantiomer B as an oil .
HRMS (m~e) 462.3543 (M , calc'd. for C32H4602:
462.3490), 377, 313, 269, 233, 227 and 91.
[ lCH30H~ 25 C. = ~16.06 4 ~ ~
EY~ PLE 16 Cis-3-[2-Hydroxy-4-~1,1-dimethylheptyl)phenyl]-trans~4-(2-aminoethyl)cyclohexanol hydrochloride _ A mixture of 1.00 gO (Z~77 mmole) of cis-3- [2-hydroxy-4-(1,1-dimethylheptyl~phenyl]-tra~s-4-(2-oxo-eth~L)cyclohexanol, 2.31 g. (30.0 mmole) of ammonium acetate and 177 mg. (2.77 mmole) of sodium cyanoboro-hydride in 10 ml. of methanol was stixred for 16 hours at 25 C. The pH of the reaction was made <2 with con-centrated hydrochloric acid and the methanol evaporatedon a rotovapor. The residue was dissolved in 200 ml.
of water and 20 ml. of methanol and the solution washed twice with 200 ml. of ether. The aqueous phase was separated and made basic (pH>10) with conce~trated sodium hydroxide, saturated with sodium chloride and extracted with 200 ml. ~ ether. This ether phase was removed, dried over magnesium sulfate and evaporated (aspirator) to an oil. The oil was dissolved in dichloromethane and excess ethereal hydrogen chloride added forming an oily precipitate which crys~allized from ether-ethyl acetate-ethanol (1-1-13 solution upon cooiing to yield 136 mg. (12%) of the title compound.
m.p.: 218-220 C. (etherr ethyl acetate, ethanol) H~MS (m/e) 361~2993 (M~, calc'd. for C23H39N02:
361.2971)~ 276, 259 and 241.
3 ~
Cis-3-[2-Benzyloxy~4-(l,l~dimethylheptyl)phenyl]~
~ trans-4-oxomethylcyclohexanol A mixture of 14.4 g. (29.9 mmole) of c~s-3-[2-benzyloxy-4~ dimethylheptyl)phenyl]-trans-4 di-methoxymethylcyclohexanol, 150 ml. of 1,4-dioxane and 150 ml. of 2N hydrochloric acid was refluxed for one hour~ The reaction was cooled and added to 2 liters of saturated sodium chloride. The aqueous quench was ex-tracted twice with 300 ml. of ether and the combined ether extract washed once with saturated sodium bicar-bona-te, dried over magnesium sulfate and evaporated on a rotovac to give a quantitative yield o~ the title compound as an oil.
IR (CHC13) 3546, 3401, 1715, 1607 and 1572 cm 1 MS (m/e) 436 (M ), 352, 345, 328, 310, 299, 259 and 91 .
P~R ~CDCl 0.82 (m, terminaL methyl), 1.22 ~s~ gem dimethyl), 2.75 (m, benzylic methine), 3.65 (m, carbinol methine), 5.01 (s, benzylic methylene), 6.83 (mr ArH), 7.06 ~d, J=8Hz, ~rH) and 7.36 (s, PhH).
Similarly, 6.3 g. (13.07 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)p}lenyl]-cis-4-dimethoxy-methylcyclohexanol (contains some of the ClS-3, trans-4 isomer) was converted to 2.05 g. (36~) of rans-3-[2-benzyloxy-4-~ -dimethylheptyl)phenyl]-clS- 4-oxomethyl-cyclohexanol and 2~2 g. (39~) of the ClS-3~ trans-4 isomer.
Separation was achieved via column chromatography on 120 g. oE silica gel eluted with 66~ ether-hexane.
Trans, cis isomer:
IR (C~C13) 1715, 1607 and 1557 cm 1.
MS ~m/e) 436 (M ), 418, 351 328 and 91.
CDC13 0.86 (m, ~erminal methyl), 1 28 (s g dimethyl), 2.7 (m, benzylic methine), 4.22 (m, carbinol methine), 5.13 (s, benzylic methylene), 6.9 (m, ArH), 7~15 ~d, J=8Hz, ArH), 7.42 (bs, PhH) and 9.42 (d, J=3Hz, C~O).
~ ~ 8 ~
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-oxomethylcyclohexanol oxime A mixture of 1.5 g. (3.44 mmole) of cis-3- r2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans--4-oxo-methylcyclohexanol and 358 mg. (5O15 mmole) of hydroxyl-amine hydrochloride in 10 ml. of pyridine was stirred at 25 C. for 24 hours. The reaction was added to one liter of 10~ hydrochloric acid and extracted with 250 ml.
ether. The ether extract was washed with 200 ml. satura~ed sodium bicarbonate, 200 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 1~40 g. (90%) of the title compound as an oil.
IR (CHC13) 3533, 3300, 1612 and 1572 cm 1.
MS (m/e) 451 (M+), 433 and 91.
PMR ~cMSl 0.86 (m~ te~minal methyl), 1.28 (s/ ~em dimethyl), 2.5-4.0 (m, 3H), 5~08 (s, banzylic methylene), 6.39 (m, lH), 6.7-7.2 (m, ArH) and 7.40 (s, PhH).
In like manner trans 3-[2 benzyloxy-4-(1,1-dimethyl-heptyl)phenyl] -cis-4 oxomethylcyclohexanol oxime was prepared in 89% (1.84 gO) yield as an oil from 2.00 g.
l4.59 mmole) o~ trans-3-[2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-cis 4-oxomethylcyclohexanol.
IR (CHC13) 3497, 3225, 1600 and 1562 cm 1.
~5 MS (m/e) 451 (M~), 433, 416, 362, 348 ~nd 91.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 4.13 (m, carbinol methine), 5~08 (s, benzylic methylene), 6.85 (m, ArH), 7.08 (d, ~--8Hz, ArH) and 7.40 (bs, PhH).
3 ~
~XAMPLE 19 Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-rans-4-(2-carbomethoxyethenyl)cyclohexanol . ~
To a 25 C. slurry of 242 mg. (10,1 mmole) of 5 sodium hydride in 20 ml. tetrahydrofuran and 10 ml.
dimethylf~rmamide was added dropwise a solution of 1.83 g.
(10 mmole) of methyl dimethylphosphonoacetate in 5 ml.
of tetrahydrofuranO The reaction was stirred 5 minutes and then a solution of 2.0 g. (4.58 mmole) of cis-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-oxomethylcyclohexanol in 5 ml. of tetrahydrofuran was added dropwise~ The reaction was stirred 15 minutes Longer and then added to 700 ml. of saturated sodium chloride. The quenched reaction was extracted with 250 ml.
o~ ether, the extract dried over magnesium sulfat~ and evaporated to an oil. The crude oil was- purified via column chromatography on 50 g. of silica gel eluted with 50~ ether-pentane to yield 1.28 g. (58%) of the title compound as an oil.
IR ~CHC13) 3389, 1709, 1650, 1610 and 1557 cm 1.
MS (m/e) 492 (M~, 407, 383, 323 and 91.
PMR ~cMcl 0.83 (m, terminal methyl), 1.25 (s, gem dimeth~l), 3~10 (m, be~zylic methine) 3.62 (s, methyl ester~, 3.62 (m, carbinol methi.ne), 5.05 (s`, benzylic meth~lene), 5.57 (d, J=16Hz, olefinic H), 6.85 (m, ArH), 7.05 (d, J=8Hz, ArH) and 7.40 (s, PhH).
_-73~
~XAMPLE 20 Cis-3-[2-Benzyloxy-4-~1,1-dimethylheptyl)phenyl]-trans-4-(2-carbamoylethenyl)cyclohexanol A mixture of 3.0 g. (6.88 mmole) of cis-3- [2-benzyloxy-4-tl,l-dimethylheptyl)phenyl~-trans-4-oxo-methylcyclohexanol and 2.43 g. (7.58 mmole) of carbæmoyl-methylenetriphenylphosphorane in 40 ml. of dichloromethane was heated at reflux for 24 hours. The reaction was concentrated and ether added to cause crystallization of triphenyLphosphine oxide. The residue was purified ~irst via column chromatography on 120 g. of silica gel eluted with ether and ~hen on 111 g. o~ neutral alumina eluted with 0-100% ethyl acetate-ether to yield 2~0 g. ~61%) of the title compound as an oil.
IR (C~C13) 3533, 1678, 1612 and 1587 cm 1 MS (m/e) 477 (M ), 460, 386, 368 and 307.
PMR ~cM~l 0.84 (m, termi~al methyl), 1.22 (s, gem dimethyl~, 3.05 (m, benzylic m~thine), 3.70 (mr carbinol methine), 5.08 (s, benzylic methylene), 5.50 (d, J=16Hæ, olefinic), 6.95 (m, ArH), 7.07 (d, J=8Hz, ArH) and 7.42 (bs, PhH).
Cis 3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-~-l2-carbomethoxyethyl~cyclohexanol A mixture of 1.28 g. (2.60 mmole) of ClS-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4 (2 carbomethoxyethenyl)cyclohexanol and 640 mg~ of 5~
Pd/C/50% H2O in 20 ml. of methanol was s~irred under one atmosphere of hydrogen for 75 minutes. The reaction was filtered through diatomaceous earth and the filtrate evapoxated. The residue was again mixed with 640 mg.
of fresh 5~ Pd/C/50~ H2O in 20 ml. of methanol and stirred under one atmosphere of hydrogen for 30 minutes, then filtered and evaporated as before. The residual oil was crystallized in ether-pentane to yield 540 mg. (51%) of the ti~le compound.
m.p.: 81-83 C. (ether-pentane) IR (CHC13~ 3521, 3289, 17Z4, 1612 and 1574 cm 1.
MS (m/e) 40~ (M+), 386, 355, 332 and 319.
PMR ~cMSl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 2.65 (m, benzylic methine), 3.46 (s, methyl ester), 3.~ (m, carbinol methine), 5.7 (broad, OH), 6.75 (m, ArH) and 7.03 (d, J=8Hz, ArH).
AnalYsis: Calc'd. for C H O :
C, 74.22; H~ 9.97.
Found: C, 73.85; H, 9.64.
Similarly, cis-3 ~2 phenyl]-trans-4-(2-carbamoylethyl)cyclohexanol was pre-.
pared in 39% (630 mg.) yield from 2.00 g. (4.19 mmole) o c -3 [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]- 0 trans-~-(2-carbamoylethenyl)cyclohexanol.
m~p.: 152-153 C. (ethyl acetate) IR (KBr) 3267, 3095, 1661, 1618 and 1575 cm 1.
MS (m/e) 389 (M ), 372, 371, 354, 353, 286, 287 and 269.
4 0 ~
PMR ~CDC13 ~ Dç-DMSO)~ 0.83 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.0 (m, benzylic methine), 3.70 (m, carbinol methine), 6.75 (m, ArH) and 7.03 ~d, J=8Hæ, AxH).
Analysis: Calcld. for C24H39NO3:
C, 73.99; H, 10.09; N, 3.60.
~ound: C, 74.10; H, 10.11; N, 3.52.
EX~MPLE 22 Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phen~l]-trans-4-(2-carboxyethyl)cyclohexanol A mixture of 1.01 gO (2.50 mmole) of cis-3-[2-hydroxy-4~(1,1-dimethylheptyl)phenyl]~trans-4-(2-carbomethoxyethyl)cyclohexanol, 25 ml. 6N sodium hydroxide and 25 ml. dioxane was heated at reflux for 40 minu~es and then cooled to 0 C~ and acidiied with 6N hydro-chloric acid. The quenched reaction was diluted with saturated sodium chloride and e~tracted several times with ether and then dichloromethane. The combined organi ex~ract wa~ evaporated and the residue recrystallized from ethyl acetate to yield 314 mg. (32%~ of the title comFound .
m.p.: 194-195 C. (ethyl acetate) IR (KBr) 3367, 3125, 1694, 1612 and 1575 cm 1.
HRMS (m/e) 390.2758 (M , calc'd. for C~H3804:
390.~760), 305, 287, 26g.
PMR (CDC13, D6-DMSO) ~TMS 0.~2 (m, terminal methyl), 1.~3 ~s, gem dimethyl), 3.50 (m, carbinol methine), 6.78 . (m, ArH) and 7.04 (d, J-8~z, AxH)~
~i7~
Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl~-trans-~ (3-aminopropyl)cyclohexanol To a 0 C. slurry of 500 mg. (13.1 mmole) of lithium S al~ninum hydride in 15 ml. of tetrahydrofuran was added a solution of 460 mg. (1.18 mmole) of cis-3-[2-hydroxy-4-(1,1-dimethylheptyl~phenyl3-trans-4-(2-carbamoylethyl~-cyclohexanol in 14 ml. of tetrahydrofuxan. The reaction was stirred at 25 C. for one hour and at re1ux Eor 20 hours. The reaction was cooled to 0 C. and quenched by the addition of a 30% solution of sodium potassium ~artrate. The quenched reaction was extracted with ethyl acetate, the extract dried over magnesium sulfate and evaporated to an oil. Crystallization of the residue in ether-ethyl acetate gave 390 mg. (88%) of the title compound.
m.p.: 137-138 C.
MS (mJe) 375 (M ), 358 and 34Q.
PMR ~CDC13 ~ D6DMSO)~TMS 0.80 (m, te~ninal methyl~, 1~22 (s, gem dimethyl), 3.34 (bs, exchangeable OH), 3.75 (m, car~inol methine), 6~75 (m, ArEI) and 7.00 (d, J=8Hz, ArH)~
The following compounds were similarly prepared:
CiS-3- ~2-hydroxy-4-(1,1-dimethylheptyl)phenyl~-tr ns-4 ~iAonetAvlcyclohex~nol in 43% (819 mg.) yield rom 1.99 g. ~5.51 mmole) of cis-3~~2 hydroxy-4-(1,1-dimethylheptyl)phenyl]-_rans-4-oxomethylcyclohexanol o~ime~
m~p.: 104-106 C. (ethyl acetate-pentane) IR (KBr) 3205, 1602 and 1572 cm 1.
HRMS (m/e) 347.2853 (M , calc'd. for C22H37NO2:
347.2815), 245, 227.
4 l~ ~
trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]~
cis-4-aminomethylcyclohexanol in 44% (427 mg.) yield . . __~
from 1~01 gO (2.80 mmole) of trans-3-[2-hydroxy-4-(l,1-dimethylheptyl)phenyl]-cis-4-oxomethylcyclohexanol oxi~e~
m.p.: 121-124 C. (ether-hexane) MS (m~e) 347 (M~), 330, 312, 245 and 227.
Cis-3 [2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-dimethylaminopropyl)cyclohexanol hydrochloride A mixture of 340 mg. ~0.906 mmole) of cis-3-~2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-amino-propyl)cyclohexanol, 268 ~1. of 37~ formaldehyde and 137 ~1. of formic acid was heated at 100 CO for 30 minutes. The reaction was cooled and added to ether and saturated sodium bicarbonate. The ether extract was dried over magnesium sulfate and evaporated to yield an oiL which was purified via column chromatography on 8 ~. of silica gel eluted with 50~ methanol-dichloro-methane to yield 78 mg. (21%~ of the free base of the title compound as a glass.
PMR ~CDCl 0.82 (m, terminal methyl), 1.22 (s gem dimethyl), 2.19 (s, N-methyls), 3.7 (m, carbinol methine), 5.55 (broad, O~), 6.75 (m, ArH) and 6.98 (d, J=~H2, ArH).
HRMS (m/e) 403.3447 (M , 100%, calc'd. for C26H45NO2:
403.3439).
The above fxee base was dissolved in ether-ethanol and excess ethereal hydrogen chloride added. The solution was then evaporated a~d the residue crystallized from ether-dichloromethane to yield 71.8 mg. (18%) of the title compound.
m.p.: 170-175 ~. (ether-dichlo~omethane) The ~ollowing compounds were prepared by the above pxocedure:
CiS- 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-. .
~rans-4-N,N-dimethylaminomethylcyclohexanol hydrochloride .
in 25~ (30mg.) yield from 100 mg. (0.288 mmole) o CiS-3 ~ 2-hydroxy-4-(1,1-dimethylheptyl)phenyl]~trans-4-aminomethylcyclohexanol.
m.p.: 202-203 C. (ether-dichloromethane) MS (m/e) 375 (~ ) 3 ~
Free Base:
PMR (CDC13)~ 0~82 (m, terminal methyl), 1.30 (s, gem dimethyl), 2.28 ~s, N,N-dimethyl), 3.75 (m, carbinol methine), 6.9 (m, ArH) and 7.12 (d, J=8Hz, ArH).
HRMS (m/e) 375.3140 (M , calc'd. for C24H41N02:
375 . 31271 -rans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-. .. r~
cis-4-N,N-dimethylaminomethylcyclohexanol hydrochloride .. .. _ ... . .. .....
in 25~ ~198 mg.) yield from 672 mg. (1.94 mmole) of trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl] -ClS-4-aminomethylcyclohe~canol.
m.p.: 176-178 C.
3) CDC13 0.82 (m, terminal methyl), 1 25 (m, gem dimethyl and methylenes), 4.26 (m, carbinol methine) and 5O6-7~2 (m, ArH~.
Free Base: -IR (C~C13) 3333, 1607 and 1563 cm 1.
MS (m/e) 375 ~M ), 330 and 245.
~ - , EXAMPLE :2 5 _ _ Trans-1-[2-~ydroxy-4-(1,1-dimethylheptyl)~henyl]-2-~(3-hydroxypropyl)cyclohexane A mixture of 1.9 g. (5.08 mmoles) of trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-2-(3-hydroxypropyl)-cyclohexanone and 10.2 ml. of hydrazine hydrate ln 20 ml.
of ethylene glycol is heated at 100 C. for an hour.
Th~ reaction was cooled to 60 Cu and 4.05 g. (72.3 m~oles) of solid potassium hydroxide added. The resultant mixture was heated for 2 hours at 200 C., then cooled and added to 500 ml. lN hydrochloric acid and 300 ml. ether. The ether extract was washed with 300 ml. saturated sodium chloride, 300 ml. saturated sodium bicarkonate, dried over magnesium sulfate and evaporated under reduced pressure lS ~aspirator) to an oil. The crude oil was purified via column chromatography on 100 gO of silica gel eluted with 70~ ether-hexane to yield 406 mg. (22~) of the title compound as a~ oil.
IR (C~C13) 3509r 3279, 1605, 1595 and 1570 cm 1.
MS (m/e) 3~0 (M+), 345, 342, 275~ 257, 233, 215, 147 and 141.
P~R ~cMcl 0.82 (m, terminal methyl), 1.25 (s, gem dimet~yl), 2,58 (m, benzylic methine), 3.46 (bt, J=6Hz, hydroxy methylene), Su0 (broad, OH), 6.67 (d, J-2Hz, ArH), 6.79 (d, J-8 and 2Hz) and 7.02 (d, J=8Hz, ArH).
4 ~3 ~
Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(2-propenyl)~ enzyloxycyclohexane . . _ . . . _ To a slurry of 214 mg. (8.92 mmole) of sodium hydride in 10 ml. dimethylformamide was added a solution of 2.0 g. (4.46 mmole) of cis-3-[2-benzyloxy-4-(1,1-di-methylheptyl)phenyl]-trans-4-(2-propenyl~cyclohexanol in 10 ml. of dimethylformamide. The reaction was stirred 5 hours and then 0.6 ml. (4.9 mmole) of benzyi bromide was added. The reaction mixture was stirred 18 hours longer and added to S00 ml. saturated sodium chloride and 500 ml. ether. The organic extract was dried o~er magnesi~ sulfate and evaporated to yield an oil which was purified via column chromatography on 100 g. of silica gel eluted with 5~ ether-hexane to yield 2.0 g (83~) of the ti~le compound as an oil.
IR (C~C13) 1639, 1600 and 1567 cm 1.
HRMS (m/e) 538.3823 tM+, calc'd. for C38H5002:
538.3798), 453, 299~ 255 and 91.
PMR ~CMCl 0.83 (m, terminal methyl), 1.24 (s, gem dimethyl), 2.85 and 3.40 (m, ether methines), 4.50 and 5.05 (s, benzylic methylenes), 4.6-5.0 and 5.2-6.1 (n, ~inyl H), 6.9 (m, ArH), 7.28 and 7.34 (bs, Ph~I).
0 ~
-8~-Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-trans-4-(3-methoxypropyl)cyclohexanol To a slurry of 172 mg. (7 mmole) of sodium hydride in lS ml. di~ethylformamide was added 2.0 g. (3.60 mmole) of CiS~3- ~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans~4-(3-hydroxypropyl)-1-benzyloxycyclohexane in lS ml.
-dimethylformamideO The reaction mixture was then heatedat 40-50 C. for 3 hours, then cooled to 25 C. and 0.663 ml. (7.0 mmole) of dimethylsulfate was added. The res~ltant mixture was stirred 18 hours at 0 C. and then ~dded to 250 ml~ saturated sodium chloride and 250 ml.
ether. The organic extract was dried over magnesium sulfate and evaporated to an oil. The crude oil was puri.~ied via colum~ chromatography on 75 g. of silica gel eluted with 20~ ether-hexane to yield 500 mg~ (24%~
of cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-tr.ans-4-(3-methoxypropyl)cyclohexanol as an oil.
PMR ~CDCl 0.83 (m, terminal methyl), 1.23 ~s, gem dimethyl), 3.20 (s, OCH3), 2~6-4.0 (m), 4.54 and 5.06 (s, benæylic methylenes~, 6.85 (m, ArH) and 7.23 (m, PhH).
Debenzylation of 500 mg. (0.874 mmole) of the pxoduct according to the procedure of Example 6 gives the title compound.
m.p.: 72-74 CO (pentane) MS (m~e) 390.3100 (M~, calc'd. for C25H42O3; 390.3123), 372, 286, 272 and 147~
PMR (CDC13) ~ 0.85 (m), 1.22 (sr gem dimethyl), 3.20 tocH3)~ 2.4-~.2 (several m), 5.05 (bs, OH), 6.8 (m, ArH) and 7.02 (d, J=8Hz, ArH).
o ~
-8~
EX~MPLE 28 Trans-3-[2-Benzyloxy-4-(R)-tl-methyl-4-phenylbutoxy)-_ phenyl]~4-~2-propenyl)cycloheptanone Using the procedure of Example 1, 23 g. (54.1 mmole) of (R~~l-hromo-2-benzyloxy-4 (l~methyl-4-phenylbutoxy)-benzene and 7.5 g. (50.0 mmole) of 4-(2-propenyl)-2-cyclohepten-l-one gave 8.14 g. ~306) o~ the title compound as an oil.
,~o [~]D = -10.61 (C = 1.077, CHC13) HRMS (m/e) 49602964 (~+, calc'd. for C34H4003:
496.2967), 405, 259, 241 and 91.
CDC13 1.22 (d, J=6~z, methyl), 4.33 (m side chain me~hine~, 4.6-5.0 and 5.2-6.0 (m, vinyl H), 5.00 (5, benzylic methylene), 6.45 (m, ArH), 7.00 (d, J=8H2, ArH), 7.24 ~s, PhH) and 7.42 (s, PhH~.
Cis-3-[2-Benzylo~y~4-(R)-(l-methyl-4-phenylbutoxy)pllenyl]-4-trans-(2-propenyl)cycloheptanol and Isomeric Alcohol . .
Using the procedure of Example 2, 8.14 g. (16.5 mmole) of trans-3-[2-benzyloxy-4-~R) (l-methyl-4-phenylbutoxy)-phenyll 4-(2-propenyl)cycloheptanone gives in order of elution 3.14 g. (39%) of the trans-3, CiS-4 isomer and 3.23 g. ~40~) o~ the title compound.
. Trans-3_2C50is 4 Isomero la]D = -10.40 (C = 1.058, CHC13) IR ~CHC13) 3508, 3448, 1626 and 1600 cm 1 HRMS (mJe) 498.3120 (M~, calc'd. for C34H4203:
~98v3123) and 91.
PMR ~cDsl 1.22 (d, J-6Hz, methyl), 2.6 (m, benzylic methylene), 3.2 (m, benzylic methine), 4.0 (m, carbinol methine), 4.25 (m, sidechain methine), 4.6~5.0 and 5.2-6.0 (m, ~inyl H), 5.02 (s, ben~ylic methylene), 6.4 (m, ArH), 7.20 and 7.38 (s, PhH).
Cis-3, Trans-4 Isomer:
~ ~25 = _g 97o (C = 1.471, CHC13) ~ R (CHC13) 3508, 3448, 1626 and 1600 cm 1.
HRMS (mje) 498.310a (M~, calc'd. for C34H~203:
498.3123), 261, 243 and 91.
PMR ~TMSl 1~22 (dl J=6Hz, methyl), 2.55 (m, benzylic 2S methylene and methine), 3.65 (m, carbinol methine~, 4.20 ~m, sidechain methine), 4.6-5.0 and 5.2-6.0 (m, vinyl ~), 5.02 (s, ben2ylic methylene), 6.4 (m, ArH), 7.00 (d, J=8Hz, ArH), 7.2 and 7.38 (s, PhH).
4 ~ ~
--~6--EX~lPLE 3 0 Cis-3-~Z-Benzyloxy 4-(R)-(l~methyl-4-phenylbutoxy)-phenyl3-4-trans-( 3 -hydroxypropyl)cycloheptanol Using the proc~dure of Example S, 1.03 g. (2.07 mmole) of CiS~3- [2-benzyloxy-4-(R)-(l-methyl-4~phenyl-butoxy)phenyl]-4-trans-(2-propenyl)cycloheptanol gave 1.0?3 g~ (100%) of the title compound as an oil.
[ 125 = _g ~3O (C = 1.051, CHC13) IR (CHC13) 3571, 3389, 1600 and 1S74 cm 1.
10HRMS (m/e) 516.3216 ~M~, calc'd. for C34H44O4:
51~.3228~.
PMR ~TMcl 1.22 (d, J=6~z, methyl), 2.7 (m, ben2ylic methylene), 3.42 (bt, C~2OH), 3.85 (m, carbinol methine), 4.35 (m, sidechain methine), 5.00 (s, benzylic methylene), lS 6.45 (m, ArH), 7.02 (d, J=8Hz, ArH), 7.25 and 7.42 (s, PhH), 4 ~ fl ~7 Cis-3-[2-Hydroxy-4-(R)~ methyl 4-ph~nylbutoxy3-phenyl~-4-tr2ns-(3-hydroxypropyl)cycloheptanol ~ ~ . . .
Using the procedure of Example 6, 1.O g. (1. 93 mmol2) 5 of CiS-3- [2-~enzyloxy-4-(R)-(l-methyl~4-phenylbutoxy)~
phenyl~-4-trans-(3-hydroxypropyl)cycloheptanol gave 500 mg. (61%) of the title compound as an oil.
[a]25 = _7.53o 5C = 0.68, CHC13) IR ~CHC13) 3508, 3333, 1600 and 1587 cm 1.
HRMS (m/e) 426.2758 (M , calc'd. for C27X3804:
426.~760~, 280, 262, 123 and 91~
PMR ~TMSl 1.22 (d, J=6Hz, methyl), 2.58 (m, benzylic methylene), 3.40 ~t, J=7Hz, CH2OH), 3.8 (m, carbinol methine), 4.15 (m, sidechain methine), 6.35 (m, ArH), 6~95 (d, J=8Hz, ArH) and 7.19 (s, PhH).
o ~
-~8-EXAMPLE 3_ Cis-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4.-(2-propenyl)-1-phthalimidocyc.loheptane To a 25 C. mixture ~f 1.00 g. (2.16 mmole) o~
trans-3-[2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl] -CiS-4-(2-propenyl)cycloheptanol, 476 mg. (3.24 ~nole) o phthalimide and 846 mgO (3.24 mmole) o~ triphenylphosphine in 1.0 ml. acetonitrile was slowly added 0.51 ml. (3.24 mmole) of diethyl azodicarboxylate. The reacticn mixture was stirred 5 hours and then dissolved in 250 ml. ether.
~rhe ether phase was washed once with 250 ml. water, once with 250 ml. saturated sodium chloride, dried over magne~ium suL~ate and evaporated to an oil. The crude oil was purified via column chromatography on 200 g. of silica gel eluted with 10~ ether hexane to yield 820 mg.
~64~) of the title compound as an oil.
IR (CHC13) 1761, 1695~ 1625, 1603 and lS63.
HRMS (m/e) 591~3799 (M , calc'd. for C40H49N03:
591.3700), 506, 353 and 91.
PMR ~CDCl 0.8 (m, terminal methyl), 1.20 (s, gem dimethyl), ~.98 (m, ben2ylic methine), 4.4 (bm, methine)~
4~5-5.0 (m, vinyl H), 5.03 (s, benzylic methylene), 5.2-6.0 (m, vinyl H), 6.78 (m, ArH), 7.02 (d, J=8Hz, ArH), .33 and 7.65 (m, ArH and PhH).
~ ~8~Q~14 Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenylJ-rans-4-(2-propenyl)-1-aminocycloheptane .
A solution of 1~0 g. (1.68 mmole) of cis-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]~~rans-4~(2-propenyl) l-phthalimidocycloheptane and 0.834 ml.
(1.68.mmole) of hydrazine hydrate in 2 ml. ethanol was heated at reflux for 20 minutes forming a precipi~ateO
The reaction was cooled, filtered and the solid washed with 200 ml. ether~ The filtrate was washed once with 100 ml. saturated sodium chloride, once with 100 ml.
50~ 2N sodium hydroxide, dried over magnesium sulfate and~evaporated to yield 770 mg. (99~) of the title compound as an oil.
IR tCHC13) 3125, 16g5, 1632~ 1600 and 1562 cm HRMS (m/e) 461.3607 (M , calc'd. for C32H~7NO:
461.3646), 420, 370, 354 and 91.
CDC13 0~8 (m, terminal methyl), 1 24 (s dimethyl)r 2.9 (m, 2H), 4.6-5O0 (m, vinyl H), 5.04 (s, benzylic methylen ), 5.2-6.1 (m, vinyl H), 6.85 (m, ArH), 7.07 (d, J-8Hz, ArH) and 7.4 (m, PhH).
Following the procedures of Example 32 and of this example, cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phen~l]-tr2ns-4-(2-propenyl)-l-aminocyclohexane is prepared from trans~3-~2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-cis-4-(2-propenyl)cyclohexanol.
~XAMPLE 34 Cis-3-[2-Benzylo~y-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)-1-acetamidocycloheptane A mlxture of 500 mg. (1.08 mmole) of cis-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2 propenyl)-l aminocyclohept~ne, 131 mg. (1.08 mmole) 4-N,N-dimethylaminopyxidine and 0.101 ml. (1.08 mmole) of acetic anhydride in 5 ml. dichloromethane was stirre~
for one hour. ~he reaction was added to 100 ml. ether and washed-twice with 100 ml. lN hydrochloric acid and twice with 100 ml. saturated sodium bicarbonate. The organic phase was dried over magnesiwm sulfate and ~vaporated to give 485 mg~ (89~) of the title compound as an oil.
IR (CHC13~ 3389, 1652, 1602 and 1562 cm 1.
HRMS (m/e~ 503.3793 (M , calc'd. for C34H49NO2:
503.3751), 418, 412, 353 and 91.
PMR ~CDCl 0.82 (mr terminal methyl), 1~22 ~s, gem dimethyl), 1.86 (s, COCH3~, 2.95 ~m, benzylic methine)~
4~02 (bm, CHN), 4.6-5.0 (m, vinyl H), 5.08 (s, benzylic methylene), 5.3-6.0 (m, vinyl H), 6.85 (m, ArH), 7.03 (d, ~-8H~, ArH) and 7.38 (m, ArH)~
o ~
-Cis-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-1-acetamidocycloheptane Using the procedure of E~ample 5, 1.7 g. (3.37 mmole) of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)-1-acetamidocycloheptane ga~e 962 mg.
(55~) of the title compound as an oil.
IR (CHC13) 3~48, 1652, 1600 and 1562 cm 1.
HRMS (m/e) 521.3813 (M , calc'd. for C34HSlNO3:
521.3856), 430, 371 and 91.
PMR CcDcl3 0.8 (mr terminal methyl), 1 20 (s gem dimethyl), ~85 (m, benzylic methine), 3.35 (m, CH2OH), 4.0 ~m, CHN)~ 5.05 (sl benzylic methylene), 5.38 (bd, NH), 6.8 (m, ArH), 7.00 (d, J=8Hz, ArH) and 7.39 (bs, PhH).
Cis-3-t4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-trans-4~(3-hydroxypropyl)-1-acetamidocycloheptane Using the procedure of Exampla 6, 960 mg. (1.84 mmole) ~0 of c iS- 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]~
tran~ -(3-hydroxypropyl)-1-acetamidocycloheptane gave 630 mg. (79%) of the title compound as an oil.
IR (CHC13) 3649, 3389l 3279, 1652, 1600 and 1562 cm 1.
HRMS (m/e) 431.3420 (M+, calc'd~ for C27H45N03:
~31.3388), 346, 287, 257, 161, 147 and 133.
PMR ~C~Cl 0.8 (mr terminal methyl), 1.20 ~s, gem dimethyl), 1.85 (s, COCH3), 2.82 (m, benzylic methine), 3.~2 (m, CH~OH), 4.0 (m, CHN), 5.6 (bd, NH), 6.75 (m, ArH) and 6.98 (d, J~8Hz, ArH).
By means of the procedures of Examples 34~ 35 and this example, cis-3-[4-(1,1-dimethylheptyl)-2-hydroxy-phenyl]-trans-(3-hydroxypropyl)-1-acet~midocyclohexane is prepared from cis-3-[2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-trans-(2-propenyl)-1-aminocyclohexane.
g) ~
Cis-3-[2-Benzyloxy-4-(1,1-dimethylhPptyl)phenyl]
trans-4-(3-hydroxypropyl)cyclohexanol bis-d-mandelate . . _ , .
A mix~ure of 31.3 g. (67.2 mmole) of CiS-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol, 25.5 g. (168 mmole) of d-mandelic acid and 1.0 g. (5.26 mmole) of p-toluene-sulfonic acid monohydrate in 500 ml. of benzene was heated at reflu~ for ll hours. Water was removed by 10 use of a sbxhlet extractor filled with 200 g. of 3A
molecular sieves. ~he reaction is cooled, added to one liter saturated sodium bicarbonate and extracted with four 500 ml. portions of ether. The combined organic extract was dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chroma-tography on 2 kg. of silica gel eluted with 40-50~ ether-hexane to yield in order of elution 18 g. (37%) of diastereomer A and 21 g~ (43~) of diastereomer B of the ti~le compound.
Diastereomer A
m~p.~ 112.5 C. (methanol) o L~]D = ~20.19 (C = 1.107, 5~ chloroform-methanol) PMR (CDC13)~ 0.84 (m, terminal methyl), 1.25 (s, gem dimethyl), 2.8 (m, benzylic methine), 3.45 (m), 4.0 (m), 4.6-5.2 (m), 5.05 (s, benæylic methylene), 6.88 (m, ArH), .27 and 7.34 (s, PhH).
_is: Calcld. for C H O :
~7 58 C, 76.81; ~I, 7.95.
Found: C, 76.49; H, 7.76.
__ In like manner, but using the same relative stoichiometric proportion of d-mandelic acid and p-toluenesulfonic acid monohydrate, 9.0 g. tl6 mmole) of cls-3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-benzyloxypropyl~cyclohexanol gave, in order of elution, 4.1 g. (37%) of diastereomer A and 4.2 g. (38%) of diastereomer B of CiS- 3-[2-benzyloxy-4-(1,1)-dimethylheptyl)phenyl]-trans-4-(3-benzyloxypropyl)-d-mandeloyloxycyclohexane as solids.
Diastereomer A:
m.p.: 56-58 C.
[~]D5 = 0.292 (C = 1.25, C1130il) PMR ~CDCl 0.80 (m, terminal methyl~, 1.20 ~s, gem dimethyl), 2.9 ~m), 3.0-3.6 (m), 4.30 (s, benzylic methylene), 4.5-5.1 (m), 5.00 (s, benzylic methylene), 6.78 (m, ArH), 6.98 (d, J=8Hz, ArH), 7.17 (s, PhH) and 7.30 (s, PhH).
L0 D stereomer B:
.p.: 65-69 C.
[~]25 = ~40 95 (C 1 21 CH OH) PMR ~cDscl 0.80 (m, terminal methyl), 1.20 (s, gem dimethyl), 2.8 (m), 3.0-3.5 (m), 4.26 (s, benzylic methylene), 4.4-5.1 (m), 4.95 (s, benzylic methylene), 6.70 (m, ArH), 6.87 (d, J=8Hz), 7.12 (s, PhH) and 7.20 (s, PhH).
o ~
- 9~ -Enantiomer A of Cis-3-[2-Benzyloxy-4-(1~1-dLmethylheptyl)-phenyl~-trans-4-(3 hydroxypropyl)cyclohexanol .. . . . _ _ A mixture of 13 g. (24.5 mmole) of diastereomer A
5 of CiS- 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol bis-d-mandelate and 13~5 g. (98~1 mmole~ of potassium carbonate in 250 ml.
methanol, 17S ml. tetrahydrofuran and 35 ml. water was stirred for 24 hours. The reaction was added to one liter saturated .~odi~m chloride and extracted twice with 500 ml. poxtions of ether. The combined organic extract was dried over magnesium sulfate and evaporated to a quankitative yield o the title compound as an oil.
~a]25 =; 34.51 (C = 1.083, methanol) PMR ~TM~l 0.82 (m, terminal methanol), 1.25 (s, gem dimethyl), 2.90 (m, benzylic methine), 3.40 (bty CH2OH), 3.7 (mr carbinol methine), 5.06 (s, benzylic methylene), 6.82 (d, J=ZHz, ArH), 6.82 (dd, J=8 and 2Hzt Ar~), 7.00 (d, J=8H~, ArH) and 7.32 (s, PhH).
Using the ahove procedure, 4.00 g. (5O79 mmole) of CiS~3- ~2-benzyloxy-4-(1,1-dime~hylheptyl)phenyl]~
rans-4-(3-benzyloxypropyl)-1-d-mandeloyloxycyclohexane,.
diastereomer A, gave a quantitative yield of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-., , ., . _. . , .... _ _ . _ _ , .
benz~loxyproPyl)cyclohexanol~ enantiomer A, as an oil~
. [a]D ~ -24.92~ (C = ~.23, C~30H) PMR 6CDC1 0~82 (m, terminal methyl), 1.22 (s, gem dLmethyl), 2.9 (m, benzylic methine), 3.23 (bt, J=6Hz, methylene), 3.7 (m, carbinol methine), 4.35 and S.00 (s~ benzylic methylenes), 6.82 (m, ArH), 7.02 (d, J=8Hz~
ArH3, 7.19 and 7.35 (s, PhH).
.~
~95 ~XAMPLE 39 Enantiomer B of Cis~3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-trans-4-(3-hydroxypropyL)cyclohexanol a~ Using the procedure of Example 38, 21 g.
(28.6 mmole) of diastereomer B of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol bis-d mandelate ga~e 13 g. (98~) of the title compound as on oii.
ta~25 = +26.30 (C = 1.051, CH30H) b. Using the procedure of Example 37, 13 g. (27~8 mmole) of the title compound and 10.6 g. (69.7 mmole~
of l-mandelic acid gave 8 g. ~39~) of diastereomer A of cis-3~ benzyloxy-4-(1,1-dimethylheptyl)phenyl~-trans~
4-(3-hydroxypropyl)cyclohexanol bis-l mandelate~
m.p. 106-107.5 C. tmethanol) P~R ~CDCl 0.83 Sterminal methyl), 1.25 (s, gem ~imathyl), 2.85 tm, be~zylic methine~, 3.40 (ml, 4.0 (m), 4.7-S.1 (m), 5.07 (s, benzylic methylene).
~nalysis. . CalC'd for C47~58O7 C~ 76~81; H, 7.95.
Folmd: C, 76.69; H, 7.86.
c. Using the procedurP of Example 38, 8.0 g.
(10.9 mmol~) of diastereomer A of CiS-3- [2-be~zylgxy~
4-(1,1-dimethylh~ptyl)phenyl~-trans-4-~3-hydroxypropyl~
cyclohexanol bis-l-mandelate gives 4.7 g. (93%) of the ti~le compound.
1]~5 = ~34.17 ~C = l.lS, CH30H) PM~ ~CDCl 0.86 (m, terminal methyl), 1.28 (s, gem dimethyl), 2 . 82 (m, benzylic methinè), 3.42 (bt, CH20H), 3.7 (m, caxbinol methine), 5.10 ts, benzylic methyle~e~, 6.9 (m, ArH), 7~10 (d, J=8Hz, ArH) and 7.40 (s, PhH)~
_96 _ Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl] trans-4-(3-hydroxypropyl)cyclohexanol, Enantiomer A _ Using the procedure of Example 6, 11.4 g. (24.5 S mmole) of enantiomer A of cis-3-[2-benzyloxy-4-(1,1-dL~ethylh p~yl)phenyl]-trans-4-(3-hydroxypropyl)~yclo-hexanol gave 8.5 g. ~93~) of the title compound.
m.p. 65-72 C. (hexane-dichloromethane) ~]D = -39.24 (C - l.OOt C~30H~
~RMS (m/e) 376.2938 (M , calc~d. for C24H4003.
376.2967)~ 304, 273, 255, 19~, 147 and 121.
PMR ~cMS1 0.83 (m, terminal methyl)~ 1.23 (s, gem dimethyl), 2.83 ~m, be~zylic methine), 3.58 (bt, CH20H), 3.7 (m, carbinol methine), 6.9 (m, ArH) and 7.00 ~d, J~8~z, ArH).
EX~MPLE 41 Cis-3-[4-(1,1-Dimethylheptyl) 2-hydroxyphenyl]-trans-4~3-hYdroxvpropYl)cyclohexanol, Enantiomer B
~ . . ~ - . . .
Using the procedure of Example 6, 4.7 g. (10.1 mmole3 o~ enantiomer B of cis-3-[2-benzyloxy-4-(1,1-dimethyl-h~pt~Il)phenyl]-transv4~3-hydroxypropyl)cyclohexanol yave 3.5 g. t52%~ of the title compound as an oil.
t1]25 ~ ~36.47a (C = 00947~ CH30~3 ~RMS (mJe) 376.2342 (M~, calc'd. for C24H4~03:
: 25 376.2967), 358, 291, 2~3 and 147.
PMR (CDC13) ~ 0.8~ (s, terminal methyl), 1.2 (s, gem dimethyl) 2.7 (m, benzylic methine), 3.41 (bt, J~7Hz, carbinol methylene), 3.78 (m, carbinol methine), 6077 (m, ArEI) and 7. no (d, J=8Hz, ArH).
t ~ 4 ~ ~
Trans-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-_ _ 5-cyanocyclohexanone To a refluxing solution of 3.~9 g~ (9.87 mmole) ~r 5-[2-benzyloxy-4-(1,1-dimethylhept~l)ph~nyl]-2-cyclo-~exen-l-one in 6.65 ml~ of ethyl acetate was added a hot ~olution of 800 mg. (11.~ mmole) of potassium cyanide =n 2 ml. wat~r and 20 3 ml. ethanol. The reacti.on was =erluxed 2 hours and then another 2.74 mmole of potassium ~vanide added. The reaction was refluxed one hour longer 2~ld then cooled and added to 400 ml. saturated sodium ~hloride-400 ml. etherO The ether extra~t was dried t~er ~nagnesium sul~ate and evaporated to yield an oil.
~he crude oil was purified via column chromatography on _60 g. of silica gel eluted with 10~ acetone-hexane to ~eld 3.02 gO (71%) o~ the itle compound.
m.p~ 79 C. (petroleum ether) IR (CHC13) ~02, 1706, 1600 and 1552 cm 1, MR (m/e) ~3L (M+), 414, 403, 346, 340 and 91.
EX~MPLE 43 Trans-3-~2~Benæyloxy-4- (19 l-dLmethylheptyl)phenyl~-. cis-5-cyanocycloh~xanol . ~
U~ing the procedure o ~xample 2, 3.02 g. (7.00 ~ole) of trans=3-[2-benzyloxy-4-(1,1-dIm~thylheptyl)-=nenyl]-5-cyanocyclohexanone was reduced to 2~66 g.
s~8~) of the title compound.
m.p. ~-102 C. (pentane~ -IR tc~Icl3) 3413, 2222, 1612 and 1575 cm 1, MS (mfe) 433 (~), . ' . ._ ., i EX~MPLE 44 Trans-3-[2 Benzyloxy-4 (l,l-dimethylheptyl)phenyl]~
trans-5-cyanocyclohexanol A mixture of 3.12 g. ~7.20 mmole) of trans-3-[2-benzylox~-4-(1,1-dimethylheptyl)phenyl] -cis-5-cyano-cyclohexanol and 808 mg~ (7.20 mmole) of potassium _-butoxide in 70 ml. of t~butanol was refluxed for 2.5 hours. The t~butanol was evapo~ated on a rotovapor and the residue dil~ted with saturated sodium chloride. The ~uenched residue was extractad with ether, the extraet dried over magnesium sulfate and evaporated to yield an oil. The crude oil was purified via column chroma-tography on 124 g. o~ silica gel eluted wi~h 10% acetone-hexane to yield 1~53 g. (44~) of the title compound.
m.p. 62-~4 C. (petroleum ether~
IR (CHC13) 2247, 1597 and 1579 cm 1, MS (m/e) 433 (M ), 348~ 342, 305 and 91.
PMR ~CDCl 0.83 (m, terminal methyl), 2.8-3.9 ~two methines), 4.25 (m, carbinol methine), 5.12 (s, benzylic methylene), 6.9 (m, ALH), 7.06 (d, J=8Hz, ArH) and 7.4 (5, PhH)o _99 _ EX~MPLE 45 Cis-3-[2-Benzyloxy~4-~ dimethylheptyl~phenyl]-5-cyanocyclohexanone .
To a 0 C. soLution of 1.43 g. (3.30 mmole1 of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-cyanocyclohexanol in 25 ml. of acetone wzs added 2.37 ml~ (6.5-mmole) of Jones's Reagent. The rPaction was stirred 20 minutes at 0 C. and then quenched by the addition of 1 ml. of isopropanol. The quenched reaction was added to 700 ml. saturated sodium chloride and extracted with 300 ml. of ether. The ether extract was dried over magnesium sulfate and evaporated to yield 1.31 g. (92~) of the title compound as an oil.
IR (CHC13) 2247, 1733, 1623 and 1584 cm 1.
MS (m/e) 431 (~ ), 416, 404l 362, 347, 340 and 91.
PMR ~CD~l 0.83 (m, terminal methyl), 1.24 (g, gem dimethyl), 2.0-3.7 (m)~ S.10 (s, benzylic methylene), 6.95 tm, ArH)/ 7.02 (dl J=8Hz) and 7.38 ~s, ArH).
0 ~
Trans-3-[2-Benzyloxy-4~ dimethylheptyl)phenyl]-trans-5-cyanocyclohexanol A mixture of 3.12 g. ~7.20 mmole~ of trans-3-[2-benzyloxy-4-(1,1-dLmethylheptyl)phenyl~ -CiS- 5-cyano-cyclohexanol and 808 mg. (7.20 mmole) o~ potassium t-butoxide in 70 ml. o~ t-butanol was refluxed for 2~5 hour~. The ~butanol was evaporated on a rotovapor and the residue dil~ted with saturated sodium chloride. The quenched residue was extracted with ether, the extract dried over magnesium sulfat~ and evaporated to yield an oil. The crude oil was purified via column chroma-tography on 124 g. o~ silica gel eluted with 10~ acetone-~exane to yield 1.53 g. ~44%) of ~he title compound.
lS m.p. 62-64 C. (petroleum ether) IR (CHCL3) 2247, 1597 and 1579 cm 1.
MS tm/e) 433 (M 3, 348~ 342, 305 and 91.
PMR ~C~Cl 0.83 (m, terminal methyl), 2.8-3.9 (two methines), 4.25 (m, carbinol methine), 5.12 (s, benzylic methylene), 6.9 (m, ArH), 7.06 (d, J=8~z, ArH) and 7.4 (s, PhH30 .
ll g~
_~9 _ EX~MPLE 45 Cis-3~[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]-5-cyanocyclohexanone To a 0 C. solution of 1043 g. (3.30 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-cyanocyclohexanol in 25 ml. of acetone W2S added 2.37 ml~ (6.5-mmole) of Jones's Reagent. The reaction was stirred 20 minutes at 0 C. and then quenched by the addition of 1 ml. of isopropanol. The quenched reaction was added ~o 700 ml. saturated sodium chloride and extracted with 300 ml. of ether. The ether ex-tract was dried over magnesium sulfate and evaporated to yield 1.31 g. (92~) of the title compound as an oil.
IR (CHC13) 2247, 1733, 1623 and 1584 cm 1.
MS (m/e) 431 ~M ), 416, 404, 362, 347, 340 and 91.
PMR CTMCl 0.83 (m, terminal methyl), 1.24 (s, gem dimethyl), 2.0-3.7 (m~, S.10 (s, benzylic methylene), 6.95 (m, ArH), 7~02 (dt J=8Hz) and 7.38 ~s, ArH).
Cis-3-~2-Benæylo~y 4-(1,1-dimethylheptyl)phenyl]-C15-5 cyanocyclohexanol Using the procedure of Example 2, 1.11 g. (2.5~
mmole) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-S cyanocyclohexanone ga~e 949 mg. (84%) of ~he title compound as ~n oil.
IR (CHC13) 3571, 3389, 2232, 1612 and 1574 cm 1.
PMR ~CDCl 0.83 (m, terminal metnyl), 1-25 (s, gem dimethyl), 3.70 (m, carbinol methine), 5~10 (s, benzylic methylene), 6.9 (m, Ar~), 7.09 (d, J=8Hæ, ArH) and 7.41 (s, PhH).
EX~MPLE 47 C.i s- 3 ~ [ 4 ~ ( 1 r 1-Dimethylheptyl)-2-hydroxyphenyl]-_ _ __5-cyanocyclohexanone Using the procedure o~ Example 6, 200 mg. (0.462 mmole) of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]~5-cyanocyclohex2none was converted ~o 133 mgO
(84~) of the title compound.
m p. 111~112 C. (ether-petroleum ether) IR (C~C13) 3571~ 3300, 2237, 1724, 1~26 and 1577 cm MS (mje) 341 (M~3, 256~ 239 and 229.
Analy~is: Calc'd. for C ~ lN02:
Cp 77.38; ~, 9.15; N, 4.10.
Found. C, 76.89; H, 9O05; ~, 4.14.
~ ~8 ~ ~4 Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]
cis-5~cyanocyclohexanol . . . ~
Using the procedure of Example 6, 235 mg. (0.542 mmole) of c iS- 3-[2-benzyloxy~4-(1,1-dimethylheptyl)-phenyl] -Cis 5-cyanocyclohexanol gave 74.5 mg. ~40~ of the title compound.
m.p~ 155 C. (dichloromethane-petroleum ether) . IR (KBr~ 3225, ~232, 1618 and 1582 cm 1.
MS (m/e) 343 (M ), 299, 258, 241 and 213 cm PM~ (CDC13, D6-DMSOj~ 0.83 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.65 (m, carbinol methi~e), 6.77 (m, ArH) and 7.00 ~d, J-8Hz, Ar~).
nalysis: Calc'd ~or C22~33~2 C, 76.92; H, 9.68; ~ 4.0~.
Found: ~, 76.51; H, 9.23; H~ 3.~5.
EXP~LE 4 9 Cis-3-[2-Benzyloxy-4-tl,l dimethylheptyl)phenyl~-5-cis-hydroxycyclohexane carboxaldehyde ~ .
To a -65 C. solution of 704 mg. (1.62 mmole) o~
CiS-3- ~2 benzyloxy-4-(1,1-dLmethylheptyl?phe~yl~-cis-S-cyanocyclohexanol in 30 ml. toluene was added 3.40 ml.
(3.4 mmole) of diisobutylaluminum hydride (lM in toluene).
The reac~ion was allowed to warm to -5 C. and was then poured onto dilute sulfuric ~cid a~d ice. ~he quenched reaction was extracted with ether, the extract dried over magnesium sul~ate and e~aporated to gi~e a quantitative yield of the titla compound as an oil.
IR (CHC13) 31~5, 1730, 1612 and 1574 cm 1.
MS (m/e) 436 (M~), 408 and 350.
CDC13 0 83 (m, terminal methyl), 1.23 (s gem dimethyl), 3.7 (m, carbinol methine), 5.11 (s, benzylic methylene), 6~85 (m, ArH), 7.35 (m, Ph~) and 9.60 (bs, C~O).
o ~
5 of CiS- 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol bis-d-mandelate and 13~5 g. (98~1 mmole~ of potassium carbonate in 250 ml.
methanol, 17S ml. tetrahydrofuran and 35 ml. water was stirred for 24 hours. The reaction was added to one liter saturated .~odi~m chloride and extracted twice with 500 ml. poxtions of ether. The combined organic extract was dried over magnesium sulfate and evaporated to a quankitative yield o the title compound as an oil.
~a]25 =; 34.51 (C = 1.083, methanol) PMR ~TM~l 0.82 (m, terminal methanol), 1.25 (s, gem dimethyl), 2.90 (m, benzylic methine), 3.40 (bty CH2OH), 3.7 (mr carbinol methine), 5.06 (s, benzylic methylene), 6.82 (d, J=ZHz, ArH), 6.82 (dd, J=8 and 2Hzt Ar~), 7.00 (d, J=8H~, ArH) and 7.32 (s, PhH).
Using the ahove procedure, 4.00 g. (5O79 mmole) of CiS~3- ~2-benzyloxy-4-(1,1-dime~hylheptyl)phenyl]~
rans-4-(3-benzyloxypropyl)-1-d-mandeloyloxycyclohexane,.
diastereomer A, gave a quantitative yield of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-., , ., . _. . , .... _ _ . _ _ , .
benz~loxyproPyl)cyclohexanol~ enantiomer A, as an oil~
. [a]D ~ -24.92~ (C = ~.23, C~30H) PMR 6CDC1 0~82 (m, terminal methyl), 1.22 (s, gem dLmethyl), 2.9 (m, benzylic methine), 3.23 (bt, J=6Hz, methylene), 3.7 (m, carbinol methine), 4.35 and S.00 (s~ benzylic methylenes), 6.82 (m, ArH), 7.02 (d, J=8Hz~
ArH3, 7.19 and 7.35 (s, PhH).
.~
~95 ~XAMPLE 39 Enantiomer B of Cis~3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-phenyl~-trans-4-(3-hydroxypropyL)cyclohexanol a~ Using the procedure of Example 38, 21 g.
(28.6 mmole) of diastereomer B of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol bis-d mandelate ga~e 13 g. (98~) of the title compound as on oii.
ta~25 = +26.30 (C = 1.051, CH30H) b. Using the procedure of Example 37, 13 g. (27~8 mmole) of the title compound and 10.6 g. (69.7 mmole~
of l-mandelic acid gave 8 g. ~39~) of diastereomer A of cis-3~ benzyloxy-4-(1,1-dimethylheptyl)phenyl~-trans~
4-(3-hydroxypropyl)cyclohexanol bis-l mandelate~
m.p. 106-107.5 C. tmethanol) P~R ~CDCl 0.83 Sterminal methyl), 1.25 (s, gem ~imathyl), 2.85 tm, be~zylic methine~, 3.40 (ml, 4.0 (m), 4.7-S.1 (m), 5.07 (s, benzylic methylene).
~nalysis. . CalC'd for C47~58O7 C~ 76~81; H, 7.95.
Folmd: C, 76.69; H, 7.86.
c. Using the procedurP of Example 38, 8.0 g.
(10.9 mmol~) of diastereomer A of CiS-3- [2-be~zylgxy~
4-(1,1-dimethylh~ptyl)phenyl~-trans-4-~3-hydroxypropyl~
cyclohexanol bis-l-mandelate gives 4.7 g. (93%) of the ti~le compound.
1]~5 = ~34.17 ~C = l.lS, CH30H) PM~ ~CDCl 0.86 (m, terminal methyl), 1.28 (s, gem dimethyl), 2 . 82 (m, benzylic methinè), 3.42 (bt, CH20H), 3.7 (m, caxbinol methine), 5.10 ts, benzylic methyle~e~, 6.9 (m, ArH), 7~10 (d, J=8Hz, ArH) and 7.40 (s, PhH)~
_96 _ Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl] trans-4-(3-hydroxypropyl)cyclohexanol, Enantiomer A _ Using the procedure of Example 6, 11.4 g. (24.5 S mmole) of enantiomer A of cis-3-[2-benzyloxy-4-(1,1-dL~ethylh p~yl)phenyl]-trans-4-(3-hydroxypropyl)~yclo-hexanol gave 8.5 g. ~93~) of the title compound.
m.p. 65-72 C. (hexane-dichloromethane) ~]D = -39.24 (C - l.OOt C~30H~
~RMS (m/e) 376.2938 (M , calc~d. for C24H4003.
376.2967)~ 304, 273, 255, 19~, 147 and 121.
PMR ~cMS1 0.83 (m, terminal methyl)~ 1.23 (s, gem dimethyl), 2.83 ~m, be~zylic methine), 3.58 (bt, CH20H), 3.7 (m, carbinol methine), 6.9 (m, ArH) and 7.00 ~d, J~8~z, ArH).
EX~MPLE 41 Cis-3-[4-(1,1-Dimethylheptyl) 2-hydroxyphenyl]-trans-4~3-hYdroxvpropYl)cyclohexanol, Enantiomer B
~ . . ~ - . . .
Using the procedure of Example 6, 4.7 g. (10.1 mmole3 o~ enantiomer B of cis-3-[2-benzyloxy-4-(1,1-dimethyl-h~pt~Il)phenyl]-transv4~3-hydroxypropyl)cyclohexanol yave 3.5 g. t52%~ of the title compound as an oil.
t1]25 ~ ~36.47a (C = 00947~ CH30~3 ~RMS (mJe) 376.2342 (M~, calc'd. for C24H4~03:
: 25 376.2967), 358, 291, 2~3 and 147.
PMR (CDC13) ~ 0.8~ (s, terminal methyl), 1.2 (s, gem dimethyl) 2.7 (m, benzylic methine), 3.41 (bt, J~7Hz, carbinol methylene), 3.78 (m, carbinol methine), 6077 (m, ArEI) and 7. no (d, J=8Hz, ArH).
t ~ 4 ~ ~
Trans-3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-_ _ 5-cyanocyclohexanone To a refluxing solution of 3.~9 g~ (9.87 mmole) ~r 5-[2-benzyloxy-4-(1,1-dimethylhept~l)ph~nyl]-2-cyclo-~exen-l-one in 6.65 ml~ of ethyl acetate was added a hot ~olution of 800 mg. (11.~ mmole) of potassium cyanide =n 2 ml. wat~r and 20 3 ml. ethanol. The reacti.on was =erluxed 2 hours and then another 2.74 mmole of potassium ~vanide added. The reaction was refluxed one hour longer 2~ld then cooled and added to 400 ml. saturated sodium ~hloride-400 ml. etherO The ether extra~t was dried t~er ~nagnesium sul~ate and evaporated to yield an oil.
~he crude oil was purified via column chromatography on _60 g. of silica gel eluted with 10~ acetone-hexane to ~eld 3.02 gO (71%) o~ the itle compound.
m.p~ 79 C. (petroleum ether) IR (CHC13) ~02, 1706, 1600 and 1552 cm 1, MR (m/e) ~3L (M+), 414, 403, 346, 340 and 91.
EX~MPLE 43 Trans-3-~2~Benæyloxy-4- (19 l-dLmethylheptyl)phenyl~-. cis-5-cyanocycloh~xanol . ~
U~ing the procedure o ~xample 2, 3.02 g. (7.00 ~ole) of trans=3-[2-benzyloxy-4-(1,1-dIm~thylheptyl)-=nenyl]-5-cyanocyclohexanone was reduced to 2~66 g.
s~8~) of the title compound.
m.p. ~-102 C. (pentane~ -IR tc~Icl3) 3413, 2222, 1612 and 1575 cm 1, MS (mfe) 433 (~), . ' . ._ ., i EX~MPLE 44 Trans-3-[2 Benzyloxy-4 (l,l-dimethylheptyl)phenyl]~
trans-5-cyanocyclohexanol A mixture of 3.12 g. ~7.20 mmole) of trans-3-[2-benzylox~-4-(1,1-dimethylheptyl)phenyl] -cis-5-cyano-cyclohexanol and 808 mg~ (7.20 mmole) of potassium _-butoxide in 70 ml. of t~butanol was refluxed for 2.5 hours. The t~butanol was evapo~ated on a rotovapor and the residue dil~ted with saturated sodium chloride. The ~uenched residue was extractad with ether, the extraet dried over magnesium sulfate and evaporated to yield an oil. The crude oil was purified via column chroma-tography on 124 g. o~ silica gel eluted wi~h 10% acetone-hexane to yield 1~53 g. (44~) of the title compound.
m.p. 62-~4 C. (petroleum ether~
IR (CHC13) 2247, 1597 and 1579 cm 1, MS (m/e) 433 (M ), 348~ 342, 305 and 91.
PMR ~CDCl 0.83 (m, terminal methyl), 2.8-3.9 ~two methines), 4.25 (m, carbinol methine), 5.12 (s, benzylic methylene), 6.9 (m, ALH), 7.06 (d, J=8Hz, ArH) and 7.4 (5, PhH)o _99 _ EX~MPLE 45 Cis-3-[2-Benzyloxy~4-~ dimethylheptyl~phenyl]-5-cyanocyclohexanone .
To a 0 C. soLution of 1.43 g. (3.30 mmole1 of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-cyanocyclohexanol in 25 ml. of acetone wzs added 2.37 ml~ (6.5-mmole) of Jones's Reagent. The rPaction was stirred 20 minutes at 0 C. and then quenched by the addition of 1 ml. of isopropanol. The quenched reaction was added to 700 ml. saturated sodium chloride and extracted with 300 ml. of ether. The ether extract was dried over magnesium sulfate and evaporated to yield 1.31 g. (92~) of the title compound as an oil.
IR (CHC13) 2247, 1733, 1623 and 1584 cm 1.
MS (m/e) 431 (~ ), 416, 404l 362, 347, 340 and 91.
PMR ~CD~l 0.83 (m, terminal methyl), 1.24 (g, gem dimethyl), 2.0-3.7 (m)~ S.10 (s, benzylic methylene), 6.95 tm, ArH)/ 7.02 (dl J=8Hz) and 7.38 ~s, ArH).
0 ~
Trans-3-[2-Benzyloxy-4~ dimethylheptyl)phenyl]-trans-5-cyanocyclohexanol A mixture of 3.12 g. ~7.20 mmole~ of trans-3-[2-benzyloxy-4-(1,1-dLmethylheptyl)phenyl~ -CiS- 5-cyano-cyclohexanol and 808 mg. (7.20 mmole) o~ potassium t-butoxide in 70 ml. o~ t-butanol was refluxed for 2~5 hour~. The ~butanol was evaporated on a rotovapor and the residue dil~ted with saturated sodium chloride. The quenched residue was extracted with ether, the extract dried over magnesium sulfat~ and evaporated to yield an oil. The crude oil was purified via column chroma-tography on 124 g. o~ silica gel eluted with 10~ acetone-~exane to yield 1.53 g. ~44%) of ~he title compound.
lS m.p. 62-64 C. (petroleum ether) IR (CHCL3) 2247, 1597 and 1579 cm 1.
MS tm/e) 433 (M 3, 348~ 342, 305 and 91.
PMR ~C~Cl 0.83 (m, terminal methyl), 2.8-3.9 (two methines), 4.25 (m, carbinol methine), 5.12 (s, benzylic methylene), 6.9 (m, ArH), 7.06 (d, J=8~z, ArH) and 7.4 (s, PhH30 .
ll g~
_~9 _ EX~MPLE 45 Cis-3~[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]-5-cyanocyclohexanone To a 0 C. solution of 1043 g. (3.30 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-cyanocyclohexanol in 25 ml. of acetone W2S added 2.37 ml~ (6.5-mmole) of Jones's Reagent. The reaction was stirred 20 minutes at 0 C. and then quenched by the addition of 1 ml. of isopropanol. The quenched reaction was added ~o 700 ml. saturated sodium chloride and extracted with 300 ml. of ether. The ether ex-tract was dried over magnesium sulfate and evaporated to yield 1.31 g. (92~) of the title compound as an oil.
IR (CHC13) 2247, 1733, 1623 and 1584 cm 1.
MS (m/e) 431 ~M ), 416, 404, 362, 347, 340 and 91.
PMR CTMCl 0.83 (m, terminal methyl), 1.24 (s, gem dimethyl), 2.0-3.7 (m~, S.10 (s, benzylic methylene), 6.95 (m, ArH), 7~02 (dt J=8Hz) and 7.38 ~s, ArH).
Cis-3-~2-Benæylo~y 4-(1,1-dimethylheptyl)phenyl]-C15-5 cyanocyclohexanol Using the procedure of Example 2, 1.11 g. (2.5~
mmole) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-S cyanocyclohexanone ga~e 949 mg. (84%) of ~he title compound as ~n oil.
IR (CHC13) 3571, 3389, 2232, 1612 and 1574 cm 1.
PMR ~CDCl 0.83 (m, terminal metnyl), 1-25 (s, gem dimethyl), 3.70 (m, carbinol methine), 5~10 (s, benzylic methylene), 6.9 (m, Ar~), 7.09 (d, J=8Hæ, ArH) and 7.41 (s, PhH).
EX~MPLE 47 C.i s- 3 ~ [ 4 ~ ( 1 r 1-Dimethylheptyl)-2-hydroxyphenyl]-_ _ __5-cyanocyclohexanone Using the procedure o~ Example 6, 200 mg. (0.462 mmole) of CiS-3- [2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]~5-cyanocyclohex2none was converted ~o 133 mgO
(84~) of the title compound.
m p. 111~112 C. (ether-petroleum ether) IR (C~C13) 3571~ 3300, 2237, 1724, 1~26 and 1577 cm MS (mje) 341 (M~3, 256~ 239 and 229.
Analy~is: Calc'd. for C ~ lN02:
Cp 77.38; ~, 9.15; N, 4.10.
Found. C, 76.89; H, 9O05; ~, 4.14.
~ ~8 ~ ~4 Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]
cis-5~cyanocyclohexanol . . . ~
Using the procedure of Example 6, 235 mg. (0.542 mmole) of c iS- 3-[2-benzyloxy~4-(1,1-dimethylheptyl)-phenyl] -Cis 5-cyanocyclohexanol gave 74.5 mg. ~40~ of the title compound.
m.p~ 155 C. (dichloromethane-petroleum ether) . IR (KBr~ 3225, ~232, 1618 and 1582 cm 1.
MS (m/e) 343 (M ), 299, 258, 241 and 213 cm PM~ (CDC13, D6-DMSOj~ 0.83 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.65 (m, carbinol methi~e), 6.77 (m, ArH) and 7.00 ~d, J-8Hz, Ar~).
nalysis: Calc'd ~or C22~33~2 C, 76.92; H, 9.68; ~ 4.0~.
Found: ~, 76.51; H, 9.23; H~ 3.~5.
EXP~LE 4 9 Cis-3-[2-Benzyloxy-4-tl,l dimethylheptyl)phenyl~-5-cis-hydroxycyclohexane carboxaldehyde ~ .
To a -65 C. solution of 704 mg. (1.62 mmole) o~
CiS-3- ~2 benzyloxy-4-(1,1-dLmethylheptyl?phe~yl~-cis-S-cyanocyclohexanol in 30 ml. toluene was added 3.40 ml.
(3.4 mmole) of diisobutylaluminum hydride (lM in toluene).
The reac~ion was allowed to warm to -5 C. and was then poured onto dilute sulfuric ~cid a~d ice. ~he quenched reaction was extracted with ether, the extract dried over magnesium sul~ate and e~aporated to gi~e a quantitative yield of the titla compound as an oil.
IR (CHC13) 31~5, 1730, 1612 and 1574 cm 1.
MS (m/e) 436 (M~), 408 and 350.
CDC13 0 83 (m, terminal methyl), 1.23 (s gem dimethyl), 3.7 (m, carbinol methine), 5.11 (s, benzylic methylene), 6~85 (m, ArH), 7.35 (m, Ph~) and 9.60 (bs, C~O).
o ~
-10 ~
ExaMpLE 50 Cis-3-[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]-cis-5-hydroxymethylcyclohexanol Using the procedure of Example 2, 700 ~g. ~1.60 mmole) of C iS -3-[2-benzyloxy-4-(1,1-dimethylheptyl~phenyl]-5-_ -hydroxycyclohexane car~oxaldehyde was converted to 208 mg. ~30~) o the title compound as an oil.
MS (m/e ) 4 3 8 (M
PMR ~CDCl 0 83 (m, terminal methyl), 1.23 (s gem dimethyl), 207 4.0 (m, 4H), 5.09 (s, benzylic methylene), 6.90 (m, .Ar~), 7.10 (d, J=8EIz, ArH) and 7.38 (s, PhH).
Cis 3 ~4~(1,1-Dimethylheptyl)-2-hydroxyphenyl]~
cis-5-hydroxymethylcyclohexanol Using the procedure of Example 6, 2Q8 mg. (0. 475 mmole) of CiS~3- [2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl] -CiS-5-hydroxymethylcyclohexanol was hydrogenolyzed to 127 mg.
(77~) of the title compound.
m.p. 126-127 C. (ether-petxoleum ether~
IR (CHC13) 3597, 3333, 1623 and 1587 cm 1, HR~S (m~e) 348.2662 (M~, calc'd. fo~ C22H36030 348. 2655), 330, 299, 287, 263 and 245.
PMR tcDcl3~ D6-DMS0)~ 0. as (m, te~minal methyl),.
1.25 (~,. gem dimethyl)~ 3.5 (m, carbinol methylene), 3.8 ~m, carbinol methine), 6.8 (m, ArH) and 7.07 (d, J=8~z ArH ) .
o ~
-:103-EX~MPLE 52 7-Oxabicyclo[4.1.0]-4-[2-~enzyloxy-4-(1,1-dimethylheptyl)phenyl]-2~heptanone . _ ~_ . . . . .
To a 0 C. solution or 3.24 g. (8.01 mmole) of 5-[2-benzyloxy-4-(1,1-dimethylheptyl~ph~nyl]-2-cyclo-hexen-l-one and 2.3 ml. (24 mmole~ o~ 30% hydroge~
peroxide i~ 80 ml. methanol was added dropwise 0u66 mlO
(3.9.6 mmole) of 6N sodium hydroxide. The reaction was stirred one hour longer at 0 C. and then added to 1000 ml. saturated sodium chlorideO The quenched reaction was extracted with 500 ml. of ether, the extract dried over magnesium ~ulfate and evaporated to yield 3.02 g. of crude product. The crude product was purified via column chromatography o~ 200 g. of silica gel eluted with 20~
ether-petroleum ether to yield in order of.elution 237 mg.
(7~ of the Ci5 isomer, 1.72 y. (51~ o~ a mixture and 1.0~ g. (30~) of the trans isomer of title compound.
CoLumn chromatography of the mixed fraction on 300 g.
o silica gel eluted with 10~ ether petroleum ether yl~lded 34 mg. tl~) o~ cis isomer and 1.56 g~ (46~) o~ the trans isomer of title compound, both as oilsO
Cis Isomer: .
IR (CHC13) 1718, 1626 and 1582 cm 1.
~S (m/e) 420 (M ), 404, 335, 31.2, 206 and 91.
PMR ~DSli 0.83 (m, terminal methyl), 1.27 (s, gem dimethyl), 2.0 2.5 (m), 2~9-3.7 (m), 5.15 (s, benzylic methylene), 6.9 tm, ArH), 7.10 (d, J=8Hz, ArH) and 7.41 (s, PhH).
Trans Isomer:
IR (CHC13) 1718, 1623 and 1577 cm 1.
MS ~mje) 420 (M ), 404, 335, 329, 316, 257 and 91.
PMR ~cDSl 0.83 (m, tenminal methyl), 1.26 (s, gem dimethyl), 2.0-2.8 (m), 3.3 (m), 3.4-4.0 (m), 5.1~ ~s, benzylic methylene), 6.9 (m, ArH), 7.07 (d, J-8Hz, ArH~
and 7.41 (s, PhH)u 0 ~1 -- 10~--In like manner, the cis- and trans-isomers of t5.1.~]-~-~2-benzyloxy-4-(l,l-dimethylheptyl)phenyl~
2-cy~loocta~one are prepared from 6-~2-benzyloxy-4-(1,1-dim2thylheptyl)phenyl~cyclohept-3-en-l-one.
r~ ~ 1 7 ~ 1 4 O d~
EX~MPLE 53 3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-hydroxycyclohexanone To a solution of 267 mg~ (0.635 ~mole) of the CLS-isomer of 7-oxabicyclo~4.1.0]-4-[2-be~æyloxy-4-(1,1-dimethylheptyl)phenyl~-2-heptanone in 20 ml. of 10%
aqueous tetrahydrofuran was added 223 mg. of alumi.num amalgam (prepared by washing 1 cm. strips of aluminum foil 15 seconds each in 2N sodi~m hydroxide, water, 0.5% mercuric chloride, water, 2N sodium hydroxide, water, 0.S% mercuric chloride, wa~er, ethanol and ether). The reaction was stirred 3 hours at 25 C. and then filtered.
through diatomaceous earth. Th~ filtrate was evaporated on a rotovapor and the residue dissolved in e~her, dried over magnesium sulfate and ev~porated~ The xesidue was purified via p.~eparative layer chromatography on two 20 cm~ x 20 cm. x 2mm. silica gel plates eluted with ether to yield 156 mg. (58%) of the title compound as an oil.
IR (CHC13) 3597, 3546, 1718, 1612 and 1577 cm 1.
MS (m/e) 422, 404, 337, 331, 319, 313 and 310.
PMR ~cMcl 0.81 (m, terminal methyl), 1.22 ( 5 ~ gem dimethyl), 3.2 (m, benzylic methine), 3.95 (m, carbinol methine), 5.0~ (s~ b~nzylic methylene), 6.9 (m, ArH),^
7.03 (d, J-8H2, ArH) and 7,38 (s, PhH).
3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-hydroxycyclohexanone .~
Using the pxocedure of Example 53, 1.47 gO
(3.5 mmole) of the trans isomer of 7-oxabicyclo[4.1.0]-4-~2-benzyloxy-4-(1,1-dimethylheptyl)pheny~]-2 heptanone gave 1.25 y. ~8Ll%) of the title compound.
m~p. 95 C. (pentane~
IR (CHC13~ 3636, 3448, 1724, 1626 and 1587 cm 1, MS (m/e) 422 (M ), 404, 337, 331, 319, 313 and 91.
PMR ~CDCl 0.85 (m, terminal methyl), 1.25 (s, gem dLmethyl)~ 2.15 (m), 2.3-2.8 (m), 3O9 (m, benzylic methine) r 4.5 (m, carbinol methine), 5.12 (s, benzylic methyLene)~ 6~9 (m, ArH), 7.08 ~d, J=8Hz, ArH~ and 7.40 ~bs, PhH)o In like manner, reduction of the cis- and trans-isomer~ of 8-oxabicyclo~5.1.0]-4-[2-benzyloxy-4~
dimethylheptyl)phenyl]-~-cyclooct~none affords the corresponding cis- and -trans 5-hydroxy derivatives.
.
~107 _ Cis-3-12-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-cyclohexan-1,5-diol, and the trans-3 cis-5 Isomer Using the procedure of Example 2, 629 mg. (1.49 mmole) of 3-12-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5~hydroxycyclohexanone (Example 54) gave 237 mg.
(38~) of the trans-3 CiS-5 isomer and 385 mg. (61%3 of the rans-5 isomer of title compound.
Cis-5 Isomer~
HRMS (m~e) 42~.3002 (M , calc'd. for C28H4003:
424.2927) PMR ~Cl 0.83. (m, terminal methyl) r 1.26 (s~ gem dimethyl), 4.25 (m, carbinol methine), 5.13 (s, benzyllc methylene), ~.9 (m, ArH), 7.12 (d, J=8Hz) and 7.41 (m, lS PhEI).
ans-5 Isomer:
H~MS (m~e) 424.2992 (M~, calc'd for C28H4003:
424.2927), 339, 231, 213 a~d 91.
CDC13 0.83 (m, terminal methyl) 1 25 (s gem dimethyl), 3~0-4.4 (m, 3H), 5.10 (s, benzylic methylene), 6.88 (d, J=2Hz, ArH), 6~88 (dd, J=8 and 2~z, ~r~ 10 ~d, J=8Hz, Ar~) and 7.40 ~m, PhH).
4 ~) 4 Cis-3-~2-Benzyloxy-4 (1,1-dimethylheptyl)ph nyl]-cis-5-cyclohexan-1,5-diol, and the cis-3-trans-5 Isomer _. . . .
Using the procedure of Example 2, 203 mg. (0.481 mmole) of 3-12-benzyloxy-4-(1,1-dimethylheptyl)phenyl~
c -5~hydroxycyclohexanone (Exampla 54) was reduced to 25 mg. (12%) of -th~ cis-3 trans-5 isomer of ti.tle com-pound and 132 mg. ~65~) of the title compound.
Cis~3-cis-5 Isomer:
HRMS 424.2974 ~M , calc'd. ~or C28H4003: 424.2927), 339, 298, 231, 213 and 91.
The remaining compounds of Example 54 are reduced to corresponding cycloheptandiols in like manner.
Cis-3-[4-(1,1-dimethylheptyl) 2-hydroxyphenyl]-_ cis~5-cy~ ohexan-1,5-diol__ _ Using the procedure of Example 6, 132 mg.
(0~311 mmole~ o~ cis-3~ [2~benzyloxy-4-(1,1-dLmethylheptyl) phenyl]-cis-5-cycloh~xan~1,5-diol was converted to 72 mg.
~69~) of the title compound.
m.p. 128 C. (ether-pentane) HRMS (m/e) 334.2517 (~ , calc'd. fo~ C21H3~03:
334~483), 298, ~49, ~31 and 213.
PMR ~TMcl 0~83 (t, terminal methyl), 1.?4 (s, gem dimethyl)~ 2.94 (m, benzylic methine), 3.35, 3.1.1 tbS, OH), 3.47-3.97 (m, carbinol methines), 6.72 (m, ArH~ and 7~00 (d, J-8Hz, ArH).
Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl)-trans-5-cyclohexan-1,5-diol . ~
Using the procedure o~ Example 6, 385 mg. (0.908 S . mmole) of _ -3-[2-benzyloxy-4-(1,l-dimethylheptyl)phenyl]-trans-5-cycLohexan-1,5-diol gave 162 mg. (53~) of ~he title compound.
m~p. 170~ C. (dichloromethane~
HRMS (m/e) 334O2513 (M+, calc'd. for C21H3~O3:
334.24~3), 298, 249, 2~1 and 213.
PMR (100 MHz, CDC13, D6-DMSO)~ 0.81 (m, terminal methyL), 1.23 (s, gem dimethyl), 3.38 ~m, benzylic methine), 3.9-4.3 ~m, carbinol methines), 6.74 (m, ArH) and 7.00 (d t J=8Hz, ArH).
_ Trans-3-[4~(1rl-Dimethylheptyl)-2-hydroxyphenyl~-cis-5-cYclohexan-1,5-diol _ _ USinCJ the procedure of Example 6, 237 mg. (0.558 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl) ____ phenyl]-cis~5-cyclohexan-1,5-diol gave 107 mg. (57%) o the title compound.
m.p~ 126-127 C. (ethex-pentane) .
HRMS (m/e~ 334.2503 (M~, calc'd. for C21H34O3:
33~.Z~83), 3l6r 298, 249 and 231~ .
~5 PMR (100 MH~, CDC13, D6-DMSO)~ 0.83 (m, terminal _ methyl), 1.24 ts, gem dimethyl), 3.82 (m, benzylic methine), 4.29 (m, carbinol methines), 6.B8 (m, ArH) and 7.06 (d, ~=8H2, ArH)c In like manner, the cycloheptandiols of Example 30 56 are debenzylated.
, .
The following compounds are prepared according to the procedure of Example 1 from the appropriate 1-bromo~2-benzyloxy 4-(Z-W)benzenes and the appropriate 4-(and 5)-2-cycloalken-1-one.
'( ~
Y ~Z--W
.. . _ . . . . . _ _ . . . . .
s Rx Ry Z W
1 CH2-CH=CH2 H (CH237 H
. 1 CH2-CH=CH~ ~ (C 2)11 H
1 CH2-CH=CH2 H ~CH~CH3)]2(CH2jS H
)2C C~2 H C(CH3)2(CH2)4 H
(C~12) 2CH~CH2 H (CH2) 8 ( 2)3 C 2 ~ C~C~3)2(C~2)6 H
(C~2)~CH CH2 H C(CE3)2(CH2)6 H
1 CH2CH=CH2 H (CH2)3 C6EI5 1 (CH2)~CH=C~2 H [C~(C~3)]2(CH235 1 CH CH-CH H (CH2)4 4-FC6H~
1 (C~2)2CH=CH2 }I CH(CH3)(CH2)3 4-ClC6H4 1 (C~I2)3CH-CH2 H CH~CH3)(C~I2)3 C6H5 1 CH2CH=CH2 H CH(CH3)(CH2)3 C6HS
1 (CH2)3CH-CH2 H CH(C2H5)(CH2~4 4-FC6H4 (CH2)3CH CH2 C(CH3)2(CH2)4 ~6H5 1 CH2CH=CH2 H (CH2)4 4-pyridyl 1 CH CH~CH H (CH2)8 C6H5 1 CH2CH=C~2 H CH(CH3)(CH2)3 2-pyr.idyl $1~L~)4 --111` _ . .
s P~Y Ry Z W
. ~
(CH2) 3C~ C~2 H ~CH2) 11 H
2 CH2CE~=CH2 H [~H (CH3) ] 2 (CH2) 5 H
2 CH2CH=CH2 H (CH23 7 H
2 (CH2) 2CH=CE12 ( 3) 2 (CH23 6 E~
2) 3CH C 2 H [CH (C~3) ~ 2 (C~2) 5 H
CH2CH=CH2 H (CH2) 4 H - C6H
CEI2CH=CH2 ( 3) ~C 2) 5 C6H5 CH CH-CH H CH (CH3) (CH2) 3 C6H5 1() 1 CH2CH=CH~ H CH (CH3) (CH2) 3 4~FC~ jH4 CH2CH=CH2 H OCH (CX3) (C}~2) 3 C6H5 (~H:2)4CH CH2 EI O H(CH3) (CH2)3 4-pyridyl (CH2) 2CH=CH2 El O (CH2) 7 4-ClC6H4 CH2CH=CH2 M (CH2) 40C~2 C6H5 1 (CH2) 3CH=CH2 H (CH2) 6 C6H5 CH2CH=CH2 H (CH2) 5 H
CH2C:H=CEI2 H (C~2) 13 H
CH2CH=CH2 H O (CH2) 3 C6~5 (CH2) ~,CH=CIIz [ ( 3) 1 2CEI2 4-pyridyl CH2CH=CH2 H CH(CH3) (CH2)4 4--pyridyi (C 2) 3C~ C~2 H (C~I2~ 7 4-pyridyl CH2CH=CH2 H O (CH2) 7 CH2CH=CEI2 H O (CH2) 11 H
(CH2) 3CH-CH;2 H OC (C~3) 2 (CH2) 5 1 CH2CH=C~I2 H (( H2)0(CH2) 7 H
(C~ 2) 4CH ~H2 ( ~2)11 H
(CH2) 2CH CH2 H ~CH;2) 3 (CH2) 4 H
CH2CEI=CH2 H O (CH2) 4 C6H5 Rx ~y Z W
2 H CH2CH=CH2 C (CH3) 2 (CH2) 6 H
2 EI CH2CH=CH2 (C 2)11 H
2 H CH2CH=CH2 [C~I~CEI3) ] 2 (CH2) 3 H
2 H CH2CH=CH2 (C~2) 11 H
q ~ ,.~ ,~_,~ "~ ~ t, `-''2"" `-"2 ~ 2~ 5 2 H CH2CH=CH;~ (CH2) 13 2 H CH2CH=CH2 (CH2) 0 (C~I2) 7 4-ClC6H4 (CE~2) 2 H C~2 H (CH2) 30CH (CH3) 2-pyridyl 1 CH2CH=CH2 H O (CH2) 5 3-pyridyl 2 CH2CH=CH2 H OCH (C~I3) (CH2) 5 H
2 CH2cH~cH;~ H O (CH2 ) 7 2 (CH2) 3CH=C~2 ( 2) 3 (CH2) 4 H
2) 3 2 ( 2) 11 X
2CH2CH=CH~2 H OCH (CH3) (C~2) 3 4FC6 2 CH2CX=CH2 H (CH2) 6 ~6H5 (C 2)3C~ CH2 H OCH(CH3) (CH2)3 2-pyridyl 2 (C~2) 3C~I CH2 H (CH2) 30CH (C~I3) 4 ClC6H4 CH (OCH3 ) 2 H ~CH ~CH3 ) ] (CH;2 ) 5 H
1 CH (OCEI3) 2 ~ (CH2) 11 H
CH(OCE~3) 2 H CH(CH3) (CH2) 3 C6H5 CH (OCH3) 2 H CH (CH3) (CH~) 3 4 -FC:6H4 CH(OCH3) ~ H (CH2) 5 H
2 H CH2CH=CH;~ (C~2) 30 (CE~) 4 H
2 H CH2CH=CH2 0tC}I2)7 H
2 EI CH2CH=CH2 OCH (C~3) (CH2) 3 C~5 2 H CH2CH=CH2 0 tCH2 ) 7 4~ClC6H4 2 H CH2CH=CH2 0CH(CH3) (CH2)3 py 2 H CH CH--CH CH (CH~) (C~2) 3 ~H5 2 El CH2CH--CH2 CH(C2~5~ (CH2) 4 4-FC6H4 s RY Ry Z W
.. _ . . ... .. .... v , ,, _ _.
2 H CH2CH=CH2 OCH(CH3)(C~2)5 H
1 CEI(OCH3~2 H C~(C~3)(CH2)3 4-pyridyl 1 CEI(OCH3)2 H OCH(C~3)(CH2)3 C6H5 1 CH(OCH3)2 H oC~tCH3)(~2)3 ~-pyridyl 1 CH(OCH3)2 H OCH(c~3)(cH2)5 H
1 CH(OCH3)2 H (C~2~40CH~ C6~5 1 CH(OCH3)2 H OtCH2)13 H
1 C~(OCH3)2 H (CH2)3 C6H5 1 ~CH2)2C~ CH2 CH3 C(CH3)2(cH2)6 H
1 CH2CH=CH2C~I3 0cH(cH3)(cH~)3 C6H5 1 (CH2)3CH CH2 C~3 O(CH2)7 H
1 C~2CH=CH2 c~3 CH(C~3)(CH2)3 C6H5 1 CH2CH=CH2 CH3 C~(cH3)(cH2)3 4-FC6H~
1 CH2C~=CH2 C~3 (~H~)30CE~CH3) 4 ClC6H4 1 CH2C~=CH2 C~3 ( H2)13 H
1 ~CH2)2CH CH2 CH3 (CH2)3 C6H5 1 (C ~)3C 2 C~3 (CX2)8 C6~5 1 (C~2)4CH CH2 ~H3 CH(CH3)(c~2)3 2-pyridyl 1 C~2CM-CH2 C~3 (CH~
1 CH2C~=CH2 c~3 ~CH2)30(CH2)4 H
2 CH2C~=C~2 CH3 OCH(CH3)(CH2)3 C~H5 2 (CH2)3CH CH2 C~3 C(C~3)2(CH2)6 H
2 CH~C~=C~2 CH3 CH(CH3)(CH2)3 4-pyridyl 2 Cx2cH=c~ CH3 O(CH2)7 H
2 CH2CH=CH2 CH3 CH(C~3)(CH2)3 4-FC6H4 The products are corl~erted to the corresponding ethylene ketals according to the procedure of Ex~mple 7.
~ ~8~
EX~MPLE 61 The cycloalkanone compounds of Example 60 are reduced according to the procedure of Example 2 to provide the corresponding 3-[2-benzyloxy-4-(Z-W) phenyl]-4-(and 5)-substituted-cycloalkanols.
The cycloalkanols o~ ~xample 61 wherein Rx or Ry .
îs alkenyl are hydrated according to the method of ~xample 5 to gi~e the corresponding 3-~2-benzyloxy-4-tZ-W)phenyl]-~-(and 5)-~-hydroxyalkylcycloalkanols.
Debenzylation o said compounds according to the catalytic hydrogenation procedure of Example 6 provides the corresponding phenols.
EXaMPLE 63 lS The cycloalkanone compounds of Example 60 wherein ~ or Ry is alkenyl are ketalized to their corres-ponding ethylene ketals by the procedure of Example 7 and then hydrated according to the procedure of Example 5 to produc~ the corresponding 3-[2-benzyl-oxy-~-(Z-W)phenyl]-4 ~or 5)~ hydroxyalkyl)cyclo-al~anone ethylene ketals. Catalytic hydrogenation according to the procedure o Example h, ~ollowed by deketalization according to Example 8, affoxds the corresponding 3-~2 hydroxy-4-(Z-W)phenyl]-4-(or 5)-~-(hydroxyalkyl)cycloalkanones.
Following the procedure of Example 9, the 3-[2-benzyloxy~4-(Z-W)phenyl]-4-(or 5)-alkenylcycloalkanones and cycloalkanols of Examples 60 and 61 are oxidized S ~o give the oorresponding compounds of the formula A ~ ~ .
Q~ z w wherein ~ B is -QCH2C~2O- or H, OH; s, Z and W are as defined in Examples 60 and 61; RX or Ry represents the ~-oxoalkyl moiety having one less carbon in the ~lkyl group than does Rx or Ry of Examples 60 and 61.
Of course, in this example, the cycloalkanones are irst ketali~ed according to the procedure of Example 7.
Also produced in this Example are coxresponding compounds, wherein Rx or Ry is carboxyalkyl having two less carbon atoms in the alkyl group than does Rx or RyJ and the corresponding ~-hydroxyketones in which the unsaturated carbon atoms of the alkenyl moiety are converted to -CO-CH20H.
Debenzylation of the thus-produced oxygenated produc~s by the procedure of Example 6 provides the cor~esponding phenols. Deketali2ation of the ketals according to the method of Example 8 gives the cor-responding cycloalkanones.
4 ~ ~
The procedure of Example 12 is used to convert the 3-t~-henzyloxy-~-(Z-w)phenyl]-4-(or 5)-1-(oxoalkyl)cyclo-alk~none ethylene ~etals of Example 64 to the corre-S sponding compounds ~herein the 4-(or 5)-substituent is a secondary alcohol group. Deketalizatio~ of the products gives the cycloalkanones.
EXAMPLE_66 The ethylene ketal compounds of Example 60 wherein Rx or Ry is alkenyl and o Example 99 are converted to correspondin~ compounds wherein Rx or ~y ls 4-(or 5) ~-(1,3-dioxolan-2-yl)alk-2-enyl by the procedure of Exa~ple L0. Cataly~ic hydrogenation of said compoun~s according to the procedure of Example 11, ~ollowed by deketalization as per Example 8, affords 3-~2-benzyloxy-4-(Z-W)phenyl]-4-(or 5)-~-(oxoalkyl)-cycloalkanones wherein the oxoalkyl group contains 3 more carbon atoms than did group Rx or Ry~
The 3-~2-hydroxy~ W)phenyl]-4-(and 5)-~-(oxo-alkyl)cycloalkanone ethylene ketals and cycloalkanols o~ Example 64 and 66 are converted to corresponding ~-(and S)-~-(aminoalXyl) derivatives by the procedure of Example 16. The products are isolated as their hydrochloride salts~
EXP~MP~E 6 8 The compounds of Examples 60 and 61 wherein R2' is dimethoxymethyl ~-CH(OCH3)2] are converted to the corresponding formyl ~CHO) compounds by the procedure o~ Example 17.
The procedures of Examples 19 and 21 are used to produce the following compounds from appropriate 3 ~2-benzyloxy-4-(Z-W)phenyl]-4-(and 5)-~-(oxoalkyl)-cycloalXanols o~ Examples 17, 64, 68 and 104 and the appropriate dialkylphosphonoalkanoic acid esters.
OH
( ~ OE~
Y ~ Z-W
s ~x Ry Z W
. . ~
( 2)3COOCH3 H (CH2)7 H
( 2)3 3 H [CH(C~3)]2(CH2)5 H
)3COOCH3 H C(C~3)2(CH2)6 H
)3COO 2HS H C(CH3)2(CH2)6 ~ 2)5COOCH3 H C(C~3)2(CH2)6 H
l ~CH2)3COOC2H5 H [C~(CH3)2]2(CH2)5 H
lS ( 2)2COOCH3 H (CH2)5 H
2 (C~2)2COOC2H5 H (CH2)5 2 H (CH2)2COOCH3 (CH2)O(CH2)7 4-ClC6H4 l (C~2)3COOCH3 ~I (C~2~
l (CEi2)5COOCH3 H C(CH3)2(CH2)6 H
2 tC}~2~3COOCH3 (CH2)11 H
l ~C~I2)5COOCH3 H C(CH3)2(C~2)6 H
( 2)5COOCH3 H (C~2)11 H
( 2)2COOCH3 H C~(~H3)(CH2)3 C5~5 l (CH2)2cOocH3 H (C~2)13 H
25( 2)2C 3 H tCH2)3 C6~5 l (C~2)2CaOCH3 H O(CH2)3 C~H5 -118 _ .. _ _ . . . . . _ .
s RY Ry Z W
(CH2)5COOCH3 H CH(CH3)(~H2~34-FC6H4 1 (CH2)4cOo~H3 H (CH2)~0CH2 C6H5 ( 2~COOCH3 ~ ( 3~2(CH2)~ H
( H2)3COOCH3 H OCH(CH3)(CH2)5 H
( 2)~COOC2H5 (~H3)(CH2)3 C6H5 H (CH2)3COOCH3 OCH(CH3)~H2~3 C6H5 1 H ~CH2)3COOCH3 OCH(CH3)(CH2)3 4-ClC~H4 1 H (CH2)2COOCH3 OCH(CH3)(CH~)5 H
1 H (CH2)3cooc2~5 (CH2)11 H
1 H (CH2)2COOC~I3 C(CH3)2(CH2)6 H
H (CHZ)3cOOcH3 C(CH3~2(C~2)6 H
2 H (CH2)3COOCH3 (CH2)11 H
2 H (CH~)3COOC~s (CH2)30(C~2)4 H
2 H (C~2]3COOCH3 0cH(cH3)(cH2)3 4~pyridyl 2 ~ ~CH2)3COOCH3 CH(C~3)(CH2)3 C6~5 1 (CH2)2COoC2H5 H OCH(CH3)(CH2)3C6H5 ( 2)3COOCH3 ~ ( 3)(CH2)34-pyridyl 1 ~CH2)3~00C2H$ H C(C~3)2(CH2)6 ~ 2)5COOCH3 H C~(~H3)(CH2)5 H
1 H (CH2)3COOCH3 OCH(C~3)CH3 C6H,5 1 H (CH2)2COOCH3 OCH(CH3)(CH2)3 4-p~ridyl 1, H (CH2)3COOCH3 CH(CH3)(CH2)3 C6H5 1 H (CH2)3COOCH3 (CH2)30(0CH2)4 H
~5 1 ~ ~ ( H2)3COOCH3 ~CH(CH3)]2(CH2)5 M
1 H (CH2)3COOC2H5 C(CH3)2(CH2)6 2 ~ (CH2)3COOC2Hs ~CI~(CH3)]2( 2)5 H
2 H (CH2)3COOCH3 (CH2)11 2 H (CH2)3COOCH3 OCH(CH3)(C~2)5 H
2 H (C~2)3COOC2H5 OCH(C~3)(CH2)3 C6H5 1 (c~I2)2coocH3 ~ ~CH2)3 ~6~5 s Rx Ry Z W
l (CH2)2COOC2H5 CH3 0( 3)2(CH2)6 ( 2)3COOCH3 CH3 ( 3)(C 2)3C6H5 l tC~I2)5COOCH3 CH3 ( 2)7 H
l (C~23~coocH3 -CH3 CH(CH3)(CH2)3C6H5 1 ~P,~2)$C~n-~3~7~ C~3 0CH(C~3)(CH2)3 4-FC6~4 l (~H2)3COo~n-c6Hl3~ C 3 (CH2)30CH(CH3) 4-ClC6H4 (C~12)3C00CH3 C~3 (CH2)l3 H
~ 2)6COOCH3 CH3 (C~2)3 C6H5 lOl (CHz)6coo(n-c6Hl3) CH3 (CH2)8 C~H5 l (CH2)4COO(n-C4Hg) CH3 C(CH3)2(CH2)6 H
l (CH2)6COOC2H5 CH3 (CH2)30(c~2)4 H
2 (CH2)3C00C2H5 C~I3 OCH(CH3)(CH2)3 C6~5 (C 2)5COOCH3 . CH3 ( 3)2(CH2)6 H
2 (CH2)4cOO(i-c3H7) CH3 CH(CH3~(CH2)3 4-pyridyl (C 2)4COOC2H5 CH3 O~CH2)7 H
2 (CH2)COOCH3 C~3 ~H(C~I3)(CH2)3 4-FC6~4 The 3-[2-benzyloxy-4-~Z-W)phenyl]-4-(and 5)-~-(oxoalkyl)cycloalkanols of Examples 17, 64, 68 and 104 are converted to corresponding 3-[2-hydroxy-4-(Z-W)-S phenyl]-4-(and 5)-~-(carbamoylalkyl)cycloalkanols by the procedures of Examples 20 and 21 using, of course, the appropriate caxbamoylal~ylene triphenylphosphorane as the Wittiy reagent.
OH
(~ o Ry ~ Z-W
.~
s Rx Ry Z W
,,, ~
1 ~CH2)2cNH2 H ~CH2)7 H
l (CH2)2CONH(C2H5) H ctcH3)2(cH2)6 H
(C 2)3CONH2 H [CH(CH3)]2(CX2)5 H
( 2)3 2 (CH2)11 H
l (CE~2)5CON~CH3)2 H C(C~3)2(C~2)6 H
1 (CH2)2CON(CH3)2 H C(CH3)2(CE12)6 H
1 (CE~2)3~ONH2 H C(CH3)2(CH2)6 H
1 (CH~)2cNH2 H (CH2)11 H
1 (C~2)4cNH2 C(CH3)2(CH2)6 l (C~2)~CONH(C2~15~ H (CH2)8 H
l (CH2)6CONH2 H [C (CH3)2~2(cEI2)5 H
l (C~2)2CONH2 H (CH2)4 C6~5 l (CE~2)2CONH(C2H5) E (CH2)4 C6H5 (CH2)2cON~H3~2 H CH(CH3)(C~2)3 C~H5 8 i~
S RX Ry Z W
2) 2 2 CH (CH3) (CH2) 3 4--FC6H4 (C~2) "~CONH2 X CH(CH3) (CH2) 44-pyridyl 2 (CH2) 2CONH2 H CH (CH3) (CH2) 3 C6H5 2 ( 2) 3 H2 H C~ (C2~5) (CE~) 4 4--FC6H4 2 (CH2) 6CONH2 H C (C~3) 2 (CH2) 6 H
2 (CH2) 4CON(CH3) ~ H (CH2) 7 H
2 (CHz)3CON(CH3)2 H OcH(cH3) (CH2)3 C~HS
2 (CH2) 3CC)N~I (C2H5) H O H (CH3) (CH2) 3 4 C6H4 1() 2 (CH2) 6C~H2 H (CH2) 30CH(CH3)4-ClC6H4 2 (CH2)4CON(CH3)2 H O(CH~)7 (CH2) 3CONH2 E~ O (CH2) 4 C6~5 (CH2)6CONH2 H OCH(CH3) (CH;~)3 4-pyridyl (CH2) 6CON(CH3) 2 H [CH (C~I3) ] 2 (CH2) 5 H
lS 1 (CH2) 2CON(CE~3) 2 H (CH2) 4 C6H5 (CH2) 2CONH2 CH ( 3) (CH2~ 3C6H5 (CH2)6CONH2 H CH(C~I3) (CH2)3C~H5 (CH2) 2CONH2 H CH (CH3) (CH2) 3 2-pyxidyl (CH2)2cON(cH3)2 H [CH(C~3)]2CH2 4-pyridyl 2 (CH2)5CONICH3)2 ~ CH(CH3) (CH2)3 C6~5 I2) 3CON~I2 ~ C (C~3) 2 (CH2) 6 H
2 (CEI2) 3CON~I (C2H5) ~I C (CH3) 2 (CH2) 6 H
2 (C~2)3CONH;~ E )cH(cH3) (C~I2)3 C6Hs 2 (CH2) 4CONH2 ~ OCH (CH3) (C~I2) 3 C6~5 7.~ 4 2 ( 2) 6~ 6H5 2 (C~2) 3CONH2 H OCH (CH3~ (CH2) 5 EI
2 (C~l~) 6CON~2 H (C~I2) 11 H
(C~[2)3CONH(C2H5) H ( 3) (CH2)3 C6H5 (CH2) 4CN~2 ~ (CH2) 30CH (CH3) 2-pyridyl 1 (CH2)3cON(cH3)2 O~CH2)5 3-pyridyl 1 4 ~) ~
. ~
s RY Ry Z W
. . . _ H (2)2CON(CH3)2 C(CH3)2(CH2)6 H
H (H2) 3CONH (C2H5) C (CE~3) 2 (CH2) 6 B
2 H (2) 3CONH2 (CH2) 3O (CX2) 4 H
2 EI (2) 3CONH2 ( 3) 2 (l:~H2) 6 H
H (CH~)3CON(CH3)2 OCH(CH3; (CE~2) 6 5 H (C 2) 2CNH2 C (CH3) 2 (~H2) 6 2 EI ( 2) 3CN~2 (CH2) 5 H
2 ( 2) 3CONH2 (C~2) 11 H
2 H (CH~)3cON~cH3~2 OC~(CH3) (CH2)S H
2 EI (2) 3CONH2 C~I (CH3) (CH2) 3 C6H5 2 H (2) 3CONH2 CH (C2H5) (CH;~) 4 4-FC6H4 (CH2)2CONH2 CH3 C(CH3)2(CH2)6 H
( CH2 ) 2CO~-lS ( 3) 2 CH3 ( 3) 2 (CH2~ 6 H
( C~;2 ) 3CO~H2 CH OCH ( CH3 ) ( CH2 ) 3 C 6EI5 ~CH2)2CONH-(C2H5) CH3 OCH(CH3) (CH2)3 C6H5 t CH2 ) 2CON ~ .
~CEI3) (n-C,~H9) CH3 0CH(CH3) (CH2)3 ~ 6~5 (CH2) 4COWH2 CH3 (CH2) 7 H
2) 3CON-3H7) 2 C~3 (C 2)13 H
(CH2)2CONH~ . -6H13) CH3 CX (CH3) (CE[2) 3 4 FC6H4 2) 2CN
~n C4H~)2 CH3 CH(C~3) (CH2)3 4-pyridyl ~C 2)2CONEI2 CH3 OC~I(CH3) (CH2)3 C6H5 2 ( CH2 ) 3 CON~
(CH3) (n-C~Hg) C~3 0CH(CH3) (CH2)3 ~6HS
2 (CE~2) 5CON--(C2E~S) 2 CH3 ( 3) 2 (CX2) 6 $1~
--123 _ ,. _ .~ . . _ . _ _ ~ _ _ s Rx Ry Z W
. . . ~
2 (CH2)2CON(CE~3)2 CH3 C(CH3) (CH2)3 4-pyridyl 2 (CH2)4CONH(C2H5) C 3 O(CH2)7 H
(CH2) 3CONH
( i -C3H7 ) CH3 CH ( CH3 ) ( CH2 ) 3 4--FC ~; H4 2 ~CE~2) 3CONX-(n C6Hl3) CH3 C (CH3) 2 (CH2~ 6 H
Reduction of the above-listed amides accorrling to 10 the procedure of Example 23 a~ords the corresponding amines .
EXAMPLE 7l The 3-L2-hydroxy-4-(z-w)phenyl]-4~(or 5~-substi-tut~d-cycloalkanones and the 3-[2-benzyloxy-4-(Z-W~-phenyll-4-(or 5)-substituted-cycloalkanones wherain the suhstituent is other than ~-oxoalkyl of Examples 6, 8, 28, 53, 5~, 60, 63 and 65 a~e converted to corresponding cycloalkanes by the procedure of Example 250 The compounds have the formula shown below wherein ~ is hydrogen or benzyl, s, Z, W and the ~-(or 5) substituents are a~ defined in said examples ~ o (~s l OR
Rx ~ Z-W
EXA~IPLE 72 Following the procedures of Examples 26 and 5, the 3-[2-benzyloxy-4-(Z-W)phenyl]-4-(or 5)-alkenyl cyclo-alkanols of Examples 2, 13 r 15 ~ 29, 5G ar.d 61 are con-verted to the corresponding benzyloxycycloalkanols accvrding to the proc~dure of Example 26 a~d the ethers then hydrated by the p.rocedure of Example 5 to give the.
corresponding 3-t2-benzYloxY-4-(Z-w)phenyl~-4-(or 5)- 0 t~~hydroxyalkyl)-l-benzyloxycycloalkanes.
The 3-[2-benzyloxy-4-(Z-W)phenyl] 4-(or 5)~
hydroxyalkyl)-l-benzyloxycycloalkanes o~ Example 72 are converted to corrasponding ~-(Cl 6alkoxy1alkyl ethers ~5 by the procedures of Examples 26 or 27.
4 ~ ~
The 3-[2-benzyloxy-4-(Z-W)phenyl]-4-(or 5)-~(al~oxyalkyl)~l-benzyloxycycloalkanes of Examples 27 and 73 are debenzylated to the corresponding 3-[2-hydroxy-4 (Z-W)phenyl3-4-~or 5)-w-(alkoxyalkyl)cycloalkanols by the procPdure of Example 6.
Using the procedures of Examples 32 and 33, the cycloalkanol compounds of Examples 61, 67 and 70 are l~ converted to corresponding 3-[2-benæyloxy-4-(Z-W)phenyl]
~-(or 5)-substi-tuted-1-aminocycloalkanes.
Acetylation of the amino compounds thus produced provides the corresponding l-acetamidocycloalkanes. Of couxse, when more than one amino group is present, as in the 3-[Z-benzyloxy-4-(Z-W)phenyl]~4-~or 5)-~-(amino alXyl)-l-aminocycloalkanes, 2 molar proportions of each of acetic anhydride and 4-N,N-dimethylaminopyridine are used.
The compounds are de~enzylated to corresponding phenoLs by the procedure of Example 6 EX~MPLE 76 Using the procedure o~ Example S, the 3-[2-benzyloxy-~-(Z-W)~henyl~-4-lor S)-alkenyl-l-acetamidocycloalkan~s of Example 75 are hydrated to corresponding ~-hydroxy-al~yl-l-acetamidocycloalkanes.
Debenzylation via the procedure of Example 6 a~fords ~he c~r~espondin~ phenol derivatives.
t :~ 8 ~
EX~MPLE 77 Tra~s-3-(2,4-Dibenzyloxyphenyl)-4-(2-propenyl)cyclohexanone Using the procedure of Example 1, 23 g. ~62.3 mmole) o~ 2,4-dibenzyloxybromobenzene and 7.2 g. (53 mmole) of ~I-(2~-propenyl~-2-cyclohexanone gave 8.56 g. (38%) of the title compound.
m.p~ 104-106 C. (diisopropyl ether) HRMS (m/e) 426.2203 ~M , calc'd. for C29H3003:
426.218t~, 335, 181 and 91.
Analysis: Calc'd~ for C29H30O3 C, 81.66; H, 7.09.
Found: C, 81.53; H, 6.85.
Trans 3-(2,4~Dibenzyloxyphenyl)-4-(2-propenyl)cyclohexane ethylene Ketal A mixture of 5.0 g. (11.73 mmole) of trans-3-(2,4-dibenzyLoxyphen~ 4~(2-propenyl~cyclohexanone, 6.5 ml.
(117 ~mole) o~ ~thylene glycol and 223 mg. (L.17 mmole) of ~-toluenesulfonic acid in 50 ml. of benzene was heated at re~lu~ for 1.5 hours. Wate.r was removed via a soxhlet ex~ractor filled with molecular ~ieves. The reaction was cooled and added to 500 ml. saturated sodium bica.rbonate and 300 ml. ether. The ether phase was ~5 sepa.rated, dried over magnesium sulfate and e.vaporated.
Trituration with diisopropyl ether-hexane gave 5.31 g.
t96%) o~ ~he title compound.
m.p. 112-113 C.
HRMS (m~e) 470.2520 ~M , calc'd. for C31H34O4:
470.2448), 387, 379, 303, 181 and 91.
Analysis: Calc'd. for C31H34O4 C, 79.12; ~, 7.28.
Found: C, 79.13; H, 7.02.
~ ~81~4 -127_ Tr~ns-3-(2,4-Dibenzyloxyphenyl)-4-(3-hydroxypropyl)cyclohexanone ethylene Ketal Using the procPdure of Example 5, 5~00 g. ~10.6 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-~2-propenyl)-cyclohexanone ethylene ketal afforded a quantitative yield of the title compound as an oil. The product was used in the procedure o Example 80 without puriication.
10Trans-3-(2,4-Di.benzyioxyphenyl)-4-(3-hydrox~propyl)cyclohexanone A mixture of 5.17 g. (10.6 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-(3-hydroxypropyl)cyclohexanon~
ethylene ketal~ 50 ml. lN hydrochloric acid and 100 ml.
lS tetrahydrofuran was heated at reflux for one hour. The reaction was cooled, par-tially evaporated on a rotovapor ancl the residue diluted with 300 ml~ saturated sodium chloride-300 ml. ethex. The ether extract was washed with ~00 ml. saturated sodium bicar~onate, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ethex to yield 4.3~ g.
(92%) of the title compound.
m.p~ 110~117 C.
Anal~sis: Calc'dO Eor C29H320~:
2S C, 78.35; H, 7.26.
_und:C, 78.17; H, 7.15.
Trans -3 - ( 2, 4 -Dihydroxyphenyl ) - 4-(3 hydroxypropyl)cyclohexanone Fol~o~ing the procedure of Example 6, 3.9 g.
(8.7~ mmole) of trans 3-(2,4-dibenzyloxyphenyl)-4-(3 hydroxyphenyl)cyclohexanone provided 2~12 gO (91%) of the title compound as an oil~
HRMS (m/e) 264.1345 (M , calc'd. for C15H20O4:
264.1356), 178, 163, 161, 155, 136 and 123.
- \
-128_ -3r 4-Dihydro-2-me~hoxy~7-hydroxy-2,4-proparlo-2~-1-beIlzopyran-9-proPanol _ A solution o~ 1.5 g. (5.68 mmole) of trans-3-(2,~L-dihydroxyphenyl)-4-(3-hydroxypropyl~cyGlohexanone in ~0 ml. methanol, 6 ml. trimethylorthoformate and 7 drops of concentrated sulfuric acid was stirxed at 0 C. for 45 minutes. The reaction was quenched by the addi tion of excess solid sodium bicarbonate and then evaporated on a rotovapor. The residue was dilutad with 300 ml. saturated sodium bicarbonate-300 ml. ether.
The ~ther ectract was dried over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 150 g. of silica gel eluted in 15 ml.
~ractions with ether to yield 1.29 g. (82~) of the title compound as an oil.
PMR ~CDC13 ~ D6-DMSO) ~ 1.88 tm), 2.85 (m), 3-35 (s, methox~), 3.45 (m, methylene), 6.22 (d, J=2~z, Ar~), 6.22 (dd~ J=8 & 2Hz, Ar~) and 6.75 (d~ J=8Hz, ArH).
HRMS (m/e) 278.1514 (M , calc'd. for C16H22O4:
~78.1512), 246, 192, 177 and 161.
~ ~8~4~
_129 _ d-3,~-Dlhydro-2-methoxy 7-~(2-octyl)oxy]-2,4-propano~2H-1 benzopyran-9-propanol _ ~ mixture of 700 mgO (2.52 mmole3 o~ 3,4-dihydro-2-methoxy-7-hydroxy-2,4-propano-2H-l-benzopyran~g~propanol 786 mg~ (3.78 mmole) of 1-2-octylmethanesulronate and 1.33 g. (10 mmole) o~ anhydrous potassium carbonate in S ml. of dimethylformamide was heated at 80 C. for 8 hours and then stirred at room temperature for 10 hours.
ExaMpLE 50 Cis-3-[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]-cis-5-hydroxymethylcyclohexanol Using the procedure of Example 2, 700 ~g. ~1.60 mmole) of C iS -3-[2-benzyloxy-4-(1,1-dimethylheptyl~phenyl]-5-_ -hydroxycyclohexane car~oxaldehyde was converted to 208 mg. ~30~) o the title compound as an oil.
MS (m/e ) 4 3 8 (M
PMR ~CDCl 0 83 (m, terminal methyl), 1.23 (s gem dimethyl), 207 4.0 (m, 4H), 5.09 (s, benzylic methylene), 6.90 (m, .Ar~), 7.10 (d, J=8EIz, ArH) and 7.38 (s, PhH).
Cis 3 ~4~(1,1-Dimethylheptyl)-2-hydroxyphenyl]~
cis-5-hydroxymethylcyclohexanol Using the procedure of Example 6, 2Q8 mg. (0. 475 mmole) of CiS~3- [2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl] -CiS-5-hydroxymethylcyclohexanol was hydrogenolyzed to 127 mg.
(77~) of the title compound.
m.p. 126-127 C. (ether-petxoleum ether~
IR (CHC13) 3597, 3333, 1623 and 1587 cm 1, HR~S (m~e) 348.2662 (M~, calc'd. fo~ C22H36030 348. 2655), 330, 299, 287, 263 and 245.
PMR tcDcl3~ D6-DMS0)~ 0. as (m, te~minal methyl),.
1.25 (~,. gem dimethyl)~ 3.5 (m, carbinol methylene), 3.8 ~m, carbinol methine), 6.8 (m, ArH) and 7.07 (d, J=8~z ArH ) .
o ~
-:103-EX~MPLE 52 7-Oxabicyclo[4.1.0]-4-[2-~enzyloxy-4-(1,1-dimethylheptyl)phenyl]-2~heptanone . _ ~_ . . . . .
To a 0 C. solution or 3.24 g. (8.01 mmole) of 5-[2-benzyloxy-4-(1,1-dimethylheptyl~ph~nyl]-2-cyclo-hexen-l-one and 2.3 ml. (24 mmole~ o~ 30% hydroge~
peroxide i~ 80 ml. methanol was added dropwise 0u66 mlO
(3.9.6 mmole) of 6N sodium hydroxide. The reaction was stirred one hour longer at 0 C. and then added to 1000 ml. saturated sodium chlorideO The quenched reaction was extracted with 500 ml. of ether, the extract dried over magnesium ~ulfate and evaporated to yield 3.02 g. of crude product. The crude product was purified via column chromatography o~ 200 g. of silica gel eluted with 20~
ether-petroleum ether to yield in order of.elution 237 mg.
(7~ of the Ci5 isomer, 1.72 y. (51~ o~ a mixture and 1.0~ g. (30~) of the trans isomer of title compound.
CoLumn chromatography of the mixed fraction on 300 g.
o silica gel eluted with 10~ ether petroleum ether yl~lded 34 mg. tl~) o~ cis isomer and 1.56 g~ (46~) o~ the trans isomer of title compound, both as oilsO
Cis Isomer: .
IR (CHC13) 1718, 1626 and 1582 cm 1.
~S (m/e) 420 (M ), 404, 335, 31.2, 206 and 91.
PMR ~DSli 0.83 (m, terminal methyl), 1.27 (s, gem dimethyl), 2.0 2.5 (m), 2~9-3.7 (m), 5.15 (s, benzylic methylene), 6.9 tm, ArH), 7.10 (d, J=8Hz, ArH) and 7.41 (s, PhH).
Trans Isomer:
IR (CHC13) 1718, 1623 and 1577 cm 1.
MS ~mje) 420 (M ), 404, 335, 329, 316, 257 and 91.
PMR ~cDSl 0.83 (m, tenminal methyl), 1.26 (s, gem dimethyl), 2.0-2.8 (m), 3.3 (m), 3.4-4.0 (m), 5.1~ ~s, benzylic methylene), 6.9 (m, ArH), 7.07 (d, J-8Hz, ArH~
and 7.41 (s, PhH)u 0 ~1 -- 10~--In like manner, the cis- and trans-isomers of t5.1.~]-~-~2-benzyloxy-4-(l,l-dimethylheptyl)phenyl~
2-cy~loocta~one are prepared from 6-~2-benzyloxy-4-(1,1-dim2thylheptyl)phenyl~cyclohept-3-en-l-one.
r~ ~ 1 7 ~ 1 4 O d~
EX~MPLE 53 3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-hydroxycyclohexanone To a solution of 267 mg~ (0.635 ~mole) of the CLS-isomer of 7-oxabicyclo~4.1.0]-4-[2-be~æyloxy-4-(1,1-dimethylheptyl)phenyl~-2-heptanone in 20 ml. of 10%
aqueous tetrahydrofuran was added 223 mg. of alumi.num amalgam (prepared by washing 1 cm. strips of aluminum foil 15 seconds each in 2N sodi~m hydroxide, water, 0.5% mercuric chloride, water, 2N sodium hydroxide, water, 0.S% mercuric chloride, wa~er, ethanol and ether). The reaction was stirred 3 hours at 25 C. and then filtered.
through diatomaceous earth. Th~ filtrate was evaporated on a rotovapor and the residue dissolved in e~her, dried over magnesium sulfate and ev~porated~ The xesidue was purified via p.~eparative layer chromatography on two 20 cm~ x 20 cm. x 2mm. silica gel plates eluted with ether to yield 156 mg. (58%) of the title compound as an oil.
IR (CHC13) 3597, 3546, 1718, 1612 and 1577 cm 1.
MS (m/e) 422, 404, 337, 331, 319, 313 and 310.
PMR ~cMcl 0.81 (m, terminal methyl), 1.22 ( 5 ~ gem dimethyl), 3.2 (m, benzylic methine), 3.95 (m, carbinol methine), 5.0~ (s~ b~nzylic methylene), 6.9 (m, ArH),^
7.03 (d, J-8H2, ArH) and 7,38 (s, PhH).
3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-hydroxycyclohexanone .~
Using the pxocedure of Example 53, 1.47 gO
(3.5 mmole) of the trans isomer of 7-oxabicyclo[4.1.0]-4-~2-benzyloxy-4-(1,1-dimethylheptyl)pheny~]-2 heptanone gave 1.25 y. ~8Ll%) of the title compound.
m~p. 95 C. (pentane~
IR (CHC13~ 3636, 3448, 1724, 1626 and 1587 cm 1, MS (m/e) 422 (M ), 404, 337, 331, 319, 313 and 91.
PMR ~CDCl 0.85 (m, terminal methyl), 1.25 (s, gem dLmethyl)~ 2.15 (m), 2.3-2.8 (m), 3O9 (m, benzylic methine) r 4.5 (m, carbinol methine), 5.12 (s, benzylic methyLene)~ 6~9 (m, ArH), 7.08 ~d, J=8Hz, ArH~ and 7.40 ~bs, PhH)o In like manner, reduction of the cis- and trans-isomer~ of 8-oxabicyclo~5.1.0]-4-[2-benzyloxy-4~
dimethylheptyl)phenyl]-~-cyclooct~none affords the corresponding cis- and -trans 5-hydroxy derivatives.
.
~107 _ Cis-3-12-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-cyclohexan-1,5-diol, and the trans-3 cis-5 Isomer Using the procedure of Example 2, 629 mg. (1.49 mmole) of 3-12-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5~hydroxycyclohexanone (Example 54) gave 237 mg.
(38~) of the trans-3 CiS-5 isomer and 385 mg. (61%3 of the rans-5 isomer of title compound.
Cis-5 Isomer~
HRMS (m~e) 42~.3002 (M , calc'd. for C28H4003:
424.2927) PMR ~Cl 0.83. (m, terminal methyl) r 1.26 (s~ gem dimethyl), 4.25 (m, carbinol methine), 5.13 (s, benzyllc methylene), ~.9 (m, ArH), 7.12 (d, J=8Hz) and 7.41 (m, lS PhEI).
ans-5 Isomer:
H~MS (m~e) 424.2992 (M~, calc'd for C28H4003:
424.2927), 339, 231, 213 a~d 91.
CDC13 0.83 (m, terminal methyl) 1 25 (s gem dimethyl), 3~0-4.4 (m, 3H), 5.10 (s, benzylic methylene), 6.88 (d, J=2Hz, ArH), 6~88 (dd, J=8 and 2~z, ~r~ 10 ~d, J=8Hz, Ar~) and 7.40 ~m, PhH).
4 ~) 4 Cis-3-~2-Benzyloxy-4 (1,1-dimethylheptyl)ph nyl]-cis-5-cyclohexan-1,5-diol, and the cis-3-trans-5 Isomer _. . . .
Using the procedure of Example 2, 203 mg. (0.481 mmole) of 3-12-benzyloxy-4-(1,1-dimethylheptyl)phenyl~
c -5~hydroxycyclohexanone (Exampla 54) was reduced to 25 mg. (12%) of -th~ cis-3 trans-5 isomer of ti.tle com-pound and 132 mg. ~65~) of the title compound.
Cis~3-cis-5 Isomer:
HRMS 424.2974 ~M , calc'd. ~or C28H4003: 424.2927), 339, 298, 231, 213 and 91.
The remaining compounds of Example 54 are reduced to corresponding cycloheptandiols in like manner.
Cis-3-[4-(1,1-dimethylheptyl) 2-hydroxyphenyl]-_ cis~5-cy~ ohexan-1,5-diol__ _ Using the procedure of Example 6, 132 mg.
(0~311 mmole~ o~ cis-3~ [2~benzyloxy-4-(1,1-dLmethylheptyl) phenyl]-cis-5-cycloh~xan~1,5-diol was converted to 72 mg.
~69~) of the title compound.
m.p. 128 C. (ether-pentane) HRMS (m/e) 334.2517 (~ , calc'd. fo~ C21H3~03:
334~483), 298, ~49, ~31 and 213.
PMR ~TMcl 0~83 (t, terminal methyl), 1.?4 (s, gem dimethyl)~ 2.94 (m, benzylic methine), 3.35, 3.1.1 tbS, OH), 3.47-3.97 (m, carbinol methines), 6.72 (m, ArH~ and 7~00 (d, J-8Hz, ArH).
Cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl)-trans-5-cyclohexan-1,5-diol . ~
Using the procedure o~ Example 6, 385 mg. (0.908 S . mmole) of _ -3-[2-benzyloxy-4-(1,l-dimethylheptyl)phenyl]-trans-5-cycLohexan-1,5-diol gave 162 mg. (53~) of ~he title compound.
m~p. 170~ C. (dichloromethane~
HRMS (m/e) 334O2513 (M+, calc'd. for C21H3~O3:
334.24~3), 298, 249, 2~1 and 213.
PMR (100 MHz, CDC13, D6-DMSO)~ 0.81 (m, terminal methyL), 1.23 (s, gem dimethyl), 3.38 ~m, benzylic methine), 3.9-4.3 ~m, carbinol methines), 6.74 (m, ArH) and 7.00 (d t J=8Hz, ArH).
_ Trans-3-[4~(1rl-Dimethylheptyl)-2-hydroxyphenyl~-cis-5-cYclohexan-1,5-diol _ _ USinCJ the procedure of Example 6, 237 mg. (0.558 mmole) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl) ____ phenyl]-cis~5-cyclohexan-1,5-diol gave 107 mg. (57%) o the title compound.
m.p~ 126-127 C. (ethex-pentane) .
HRMS (m/e~ 334.2503 (M~, calc'd. for C21H34O3:
33~.Z~83), 3l6r 298, 249 and 231~ .
~5 PMR (100 MH~, CDC13, D6-DMSO)~ 0.83 (m, terminal _ methyl), 1.24 ts, gem dimethyl), 3.82 (m, benzylic methine), 4.29 (m, carbinol methines), 6.B8 (m, ArH) and 7.06 (d, ~=8H2, ArH)c In like manner, the cycloheptandiols of Example 30 56 are debenzylated.
, .
The following compounds are prepared according to the procedure of Example 1 from the appropriate 1-bromo~2-benzyloxy 4-(Z-W)benzenes and the appropriate 4-(and 5)-2-cycloalken-1-one.
'( ~
Y ~Z--W
.. . _ . . . . . _ _ . . . . .
s Rx Ry Z W
1 CH2-CH=CH2 H (CH237 H
. 1 CH2-CH=CH~ ~ (C 2)11 H
1 CH2-CH=CH2 H ~CH~CH3)]2(CH2jS H
)2C C~2 H C(CH3)2(CH2)4 H
(C~12) 2CH~CH2 H (CH2) 8 ( 2)3 C 2 ~ C~C~3)2(C~2)6 H
(C~2)~CH CH2 H C(CE3)2(CH2)6 H
1 CH2CH=CH2 H (CH2)3 C6EI5 1 (CH2)~CH=C~2 H [C~(C~3)]2(CH235 1 CH CH-CH H (CH2)4 4-FC6H~
1 (C~2)2CH=CH2 }I CH(CH3)(CH2)3 4-ClC6H4 1 (C~I2)3CH-CH2 H CH~CH3)(C~I2)3 C6H5 1 CH2CH=CH2 H CH(CH3)(CH2)3 C6HS
1 (CH2)3CH-CH2 H CH(C2H5)(CH2~4 4-FC6H4 (CH2)3CH CH2 C(CH3)2(CH2)4 ~6H5 1 CH2CH=CH2 H (CH2)4 4-pyridyl 1 CH CH~CH H (CH2)8 C6H5 1 CH2CH=C~2 H CH(CH3)(CH2)3 2-pyr.idyl $1~L~)4 --111` _ . .
s P~Y Ry Z W
. ~
(CH2) 3C~ C~2 H ~CH2) 11 H
2 CH2CE~=CH2 H [~H (CH3) ] 2 (CH2) 5 H
2 CH2CH=CH2 H (CH23 7 H
2 (CH2) 2CH=CE12 ( 3) 2 (CH23 6 E~
2) 3CH C 2 H [CH (C~3) ~ 2 (C~2) 5 H
CH2CH=CH2 H (CH2) 4 H - C6H
CEI2CH=CH2 ( 3) ~C 2) 5 C6H5 CH CH-CH H CH (CH3) (CH2) 3 C6H5 1() 1 CH2CH=CH~ H CH (CH3) (CH2) 3 4~FC~ jH4 CH2CH=CH2 H OCH (CX3) (C}~2) 3 C6H5 (~H:2)4CH CH2 EI O H(CH3) (CH2)3 4-pyridyl (CH2) 2CH=CH2 El O (CH2) 7 4-ClC6H4 CH2CH=CH2 M (CH2) 40C~2 C6H5 1 (CH2) 3CH=CH2 H (CH2) 6 C6H5 CH2CH=CH2 H (CH2) 5 H
CH2C:H=CEI2 H (C~2) 13 H
CH2CH=CH2 H O (CH2) 3 C6~5 (CH2) ~,CH=CIIz [ ( 3) 1 2CEI2 4-pyridyl CH2CH=CH2 H CH(CH3) (CH2)4 4--pyridyi (C 2) 3C~ C~2 H (C~I2~ 7 4-pyridyl CH2CH=CH2 H O (CH2) 7 CH2CH=CEI2 H O (CH2) 11 H
(CH2) 3CH-CH;2 H OC (C~3) 2 (CH2) 5 1 CH2CH=C~I2 H (( H2)0(CH2) 7 H
(C~ 2) 4CH ~H2 ( ~2)11 H
(CH2) 2CH CH2 H ~CH;2) 3 (CH2) 4 H
CH2CEI=CH2 H O (CH2) 4 C6H5 Rx ~y Z W
2 H CH2CH=CH2 C (CH3) 2 (CH2) 6 H
2 EI CH2CH=CH2 (C 2)11 H
2 H CH2CH=CH2 [C~I~CEI3) ] 2 (CH2) 3 H
2 H CH2CH=CH2 (C~2) 11 H
q ~ ,.~ ,~_,~ "~ ~ t, `-''2"" `-"2 ~ 2~ 5 2 H CH2CH=CH;~ (CH2) 13 2 H CH2CH=CH2 (CH2) 0 (C~I2) 7 4-ClC6H4 (CE~2) 2 H C~2 H (CH2) 30CH (CH3) 2-pyridyl 1 CH2CH=CH2 H O (CH2) 5 3-pyridyl 2 CH2CH=CH2 H OCH (C~I3) (CH2) 5 H
2 CH2cH~cH;~ H O (CH2 ) 7 2 (CH2) 3CH=C~2 ( 2) 3 (CH2) 4 H
2) 3 2 ( 2) 11 X
2CH2CH=CH~2 H OCH (CH3) (C~2) 3 4FC6 2 CH2CX=CH2 H (CH2) 6 ~6H5 (C 2)3C~ CH2 H OCH(CH3) (CH2)3 2-pyridyl 2 (C~2) 3C~I CH2 H (CH2) 30CH (C~I3) 4 ClC6H4 CH (OCH3 ) 2 H ~CH ~CH3 ) ] (CH;2 ) 5 H
1 CH (OCEI3) 2 ~ (CH2) 11 H
CH(OCE~3) 2 H CH(CH3) (CH2) 3 C6H5 CH (OCH3) 2 H CH (CH3) (CH~) 3 4 -FC:6H4 CH(OCH3) ~ H (CH2) 5 H
2 H CH2CH=CH;~ (C~2) 30 (CE~) 4 H
2 H CH2CH=CH2 0tC}I2)7 H
2 EI CH2CH=CH2 OCH (C~3) (CH2) 3 C~5 2 H CH2CH=CH2 0 tCH2 ) 7 4~ClC6H4 2 H CH2CH=CH2 0CH(CH3) (CH2)3 py 2 H CH CH--CH CH (CH~) (C~2) 3 ~H5 2 El CH2CH--CH2 CH(C2~5~ (CH2) 4 4-FC6H4 s RY Ry Z W
.. _ . . ... .. .... v , ,, _ _.
2 H CH2CH=CH2 OCH(CH3)(C~2)5 H
1 CEI(OCH3~2 H C~(C~3)(CH2)3 4-pyridyl 1 CEI(OCH3)2 H OCH(C~3)(CH2)3 C6H5 1 CH(OCH3)2 H oC~tCH3)(~2)3 ~-pyridyl 1 CH(OCH3)2 H OCH(c~3)(cH2)5 H
1 CH(OCH3)2 H (C~2~40CH~ C6~5 1 CH(OCH3)2 H OtCH2)13 H
1 C~(OCH3)2 H (CH2)3 C6H5 1 ~CH2)2C~ CH2 CH3 C(CH3)2(cH2)6 H
1 CH2CH=CH2C~I3 0cH(cH3)(cH~)3 C6H5 1 (CH2)3CH CH2 C~3 O(CH2)7 H
1 C~2CH=CH2 c~3 CH(C~3)(CH2)3 C6H5 1 CH2CH=CH2 CH3 C~(cH3)(cH2)3 4-FC6H~
1 CH2C~=CH2 C~3 (~H~)30CE~CH3) 4 ClC6H4 1 CH2C~=CH2 C~3 ( H2)13 H
1 ~CH2)2CH CH2 CH3 (CH2)3 C6H5 1 (C ~)3C 2 C~3 (CX2)8 C6~5 1 (C~2)4CH CH2 ~H3 CH(CH3)(c~2)3 2-pyridyl 1 C~2CM-CH2 C~3 (CH~
1 CH2C~=CH2 c~3 ~CH2)30(CH2)4 H
2 CH2C~=C~2 CH3 OCH(CH3)(CH2)3 C~H5 2 (CH2)3CH CH2 C~3 C(C~3)2(CH2)6 H
2 CH~C~=C~2 CH3 CH(CH3)(CH2)3 4-pyridyl 2 Cx2cH=c~ CH3 O(CH2)7 H
2 CH2CH=CH2 CH3 CH(C~3)(CH2)3 4-FC6H4 The products are corl~erted to the corresponding ethylene ketals according to the procedure of Ex~mple 7.
~ ~8~
EX~MPLE 61 The cycloalkanone compounds of Example 60 are reduced according to the procedure of Example 2 to provide the corresponding 3-[2-benzyloxy-4-(Z-W) phenyl]-4-(and 5)-substituted-cycloalkanols.
The cycloalkanols o~ ~xample 61 wherein Rx or Ry .
îs alkenyl are hydrated according to the method of ~xample 5 to gi~e the corresponding 3-~2-benzyloxy-4-tZ-W)phenyl]-~-(and 5)-~-hydroxyalkylcycloalkanols.
Debenzylation o said compounds according to the catalytic hydrogenation procedure of Example 6 provides the corresponding phenols.
EXaMPLE 63 lS The cycloalkanone compounds of Example 60 wherein ~ or Ry is alkenyl are ketalized to their corres-ponding ethylene ketals by the procedure of Example 7 and then hydrated according to the procedure of Example 5 to produc~ the corresponding 3-[2-benzyl-oxy-~-(Z-W)phenyl]-4 ~or 5)~ hydroxyalkyl)cyclo-al~anone ethylene ketals. Catalytic hydrogenation according to the procedure o Example h, ~ollowed by deketalization according to Example 8, affoxds the corresponding 3-~2 hydroxy-4-(Z-W)phenyl]-4-(or 5)-~-(hydroxyalkyl)cycloalkanones.
Following the procedure of Example 9, the 3-[2-benzyloxy~4-(Z-W)phenyl]-4-(or 5)-alkenylcycloalkanones and cycloalkanols of Examples 60 and 61 are oxidized S ~o give the oorresponding compounds of the formula A ~ ~ .
Q~ z w wherein ~ B is -QCH2C~2O- or H, OH; s, Z and W are as defined in Examples 60 and 61; RX or Ry represents the ~-oxoalkyl moiety having one less carbon in the ~lkyl group than does Rx or Ry of Examples 60 and 61.
Of course, in this example, the cycloalkanones are irst ketali~ed according to the procedure of Example 7.
Also produced in this Example are coxresponding compounds, wherein Rx or Ry is carboxyalkyl having two less carbon atoms in the alkyl group than does Rx or RyJ and the corresponding ~-hydroxyketones in which the unsaturated carbon atoms of the alkenyl moiety are converted to -CO-CH20H.
Debenzylation of the thus-produced oxygenated produc~s by the procedure of Example 6 provides the cor~esponding phenols. Deketali2ation of the ketals according to the method of Example 8 gives the cor-responding cycloalkanones.
4 ~ ~
The procedure of Example 12 is used to convert the 3-t~-henzyloxy-~-(Z-w)phenyl]-4-(or 5)-1-(oxoalkyl)cyclo-alk~none ethylene ~etals of Example 64 to the corre-S sponding compounds ~herein the 4-(or 5)-substituent is a secondary alcohol group. Deketalizatio~ of the products gives the cycloalkanones.
EXAMPLE_66 The ethylene ketal compounds of Example 60 wherein Rx or Ry is alkenyl and o Example 99 are converted to correspondin~ compounds wherein Rx or ~y ls 4-(or 5) ~-(1,3-dioxolan-2-yl)alk-2-enyl by the procedure of Exa~ple L0. Cataly~ic hydrogenation of said compoun~s according to the procedure of Example 11, ~ollowed by deketalization as per Example 8, affords 3-~2-benzyloxy-4-(Z-W)phenyl]-4-(or 5)-~-(oxoalkyl)-cycloalkanones wherein the oxoalkyl group contains 3 more carbon atoms than did group Rx or Ry~
The 3-~2-hydroxy~ W)phenyl]-4-(and 5)-~-(oxo-alkyl)cycloalkanone ethylene ketals and cycloalkanols o~ Example 64 and 66 are converted to corresponding ~-(and S)-~-(aminoalXyl) derivatives by the procedure of Example 16. The products are isolated as their hydrochloride salts~
EXP~MP~E 6 8 The compounds of Examples 60 and 61 wherein R2' is dimethoxymethyl ~-CH(OCH3)2] are converted to the corresponding formyl ~CHO) compounds by the procedure o~ Example 17.
The procedures of Examples 19 and 21 are used to produce the following compounds from appropriate 3 ~2-benzyloxy-4-(Z-W)phenyl]-4-(and 5)-~-(oxoalkyl)-cycloalXanols o~ Examples 17, 64, 68 and 104 and the appropriate dialkylphosphonoalkanoic acid esters.
OH
( ~ OE~
Y ~ Z-W
s ~x Ry Z W
. . ~
( 2)3COOCH3 H (CH2)7 H
( 2)3 3 H [CH(C~3)]2(CH2)5 H
)3COOCH3 H C(C~3)2(CH2)6 H
)3COO 2HS H C(CH3)2(CH2)6 ~ 2)5COOCH3 H C(C~3)2(CH2)6 H
l ~CH2)3COOC2H5 H [C~(CH3)2]2(CH2)5 H
lS ( 2)2COOCH3 H (CH2)5 H
2 (C~2)2COOC2H5 H (CH2)5 2 H (CH2)2COOCH3 (CH2)O(CH2)7 4-ClC6H4 l (C~2)3COOCH3 ~I (C~2~
l (CEi2)5COOCH3 H C(CH3)2(CH2)6 H
2 tC}~2~3COOCH3 (CH2)11 H
l ~C~I2)5COOCH3 H C(CH3)2(C~2)6 H
( 2)5COOCH3 H (C~2)11 H
( 2)2COOCH3 H C~(~H3)(CH2)3 C5~5 l (CH2)2cOocH3 H (C~2)13 H
25( 2)2C 3 H tCH2)3 C6~5 l (C~2)2CaOCH3 H O(CH2)3 C~H5 -118 _ .. _ _ . . . . . _ .
s RY Ry Z W
(CH2)5COOCH3 H CH(CH3)(~H2~34-FC6H4 1 (CH2)4cOo~H3 H (CH2)~0CH2 C6H5 ( 2~COOCH3 ~ ( 3~2(CH2)~ H
( H2)3COOCH3 H OCH(CH3)(CH2)5 H
( 2)~COOC2H5 (~H3)(CH2)3 C6H5 H (CH2)3COOCH3 OCH(CH3)~H2~3 C6H5 1 H ~CH2)3COOCH3 OCH(CH3)(CH2)3 4-ClC~H4 1 H (CH2)2COOCH3 OCH(CH3)(CH~)5 H
1 H (CH2)3cooc2~5 (CH2)11 H
1 H (CH2)2COOC~I3 C(CH3)2(CH2)6 H
H (CHZ)3cOOcH3 C(CH3~2(C~2)6 H
2 H (CH2)3COOCH3 (CH2)11 H
2 H (CH~)3COOC~s (CH2)30(C~2)4 H
2 H (C~2]3COOCH3 0cH(cH3)(cH2)3 4~pyridyl 2 ~ ~CH2)3COOCH3 CH(C~3)(CH2)3 C6~5 1 (CH2)2COoC2H5 H OCH(CH3)(CH2)3C6H5 ( 2)3COOCH3 ~ ( 3)(CH2)34-pyridyl 1 ~CH2)3~00C2H$ H C(C~3)2(CH2)6 ~ 2)5COOCH3 H C~(~H3)(CH2)5 H
1 H (CH2)3COOCH3 OCH(C~3)CH3 C6H,5 1 H (CH2)2COOCH3 OCH(CH3)(CH2)3 4-p~ridyl 1, H (CH2)3COOCH3 CH(CH3)(CH2)3 C6H5 1 H (CH2)3COOCH3 (CH2)30(0CH2)4 H
~5 1 ~ ~ ( H2)3COOCH3 ~CH(CH3)]2(CH2)5 M
1 H (CH2)3COOC2H5 C(CH3)2(CH2)6 2 ~ (CH2)3COOC2Hs ~CI~(CH3)]2( 2)5 H
2 H (CH2)3COOCH3 (CH2)11 2 H (CH2)3COOCH3 OCH(CH3)(C~2)5 H
2 H (C~2)3COOC2H5 OCH(C~3)(CH2)3 C6H5 1 (c~I2)2coocH3 ~ ~CH2)3 ~6~5 s Rx Ry Z W
l (CH2)2COOC2H5 CH3 0( 3)2(CH2)6 ( 2)3COOCH3 CH3 ( 3)(C 2)3C6H5 l tC~I2)5COOCH3 CH3 ( 2)7 H
l (C~23~coocH3 -CH3 CH(CH3)(CH2)3C6H5 1 ~P,~2)$C~n-~3~7~ C~3 0CH(C~3)(CH2)3 4-FC6~4 l (~H2)3COo~n-c6Hl3~ C 3 (CH2)30CH(CH3) 4-ClC6H4 (C~12)3C00CH3 C~3 (CH2)l3 H
~ 2)6COOCH3 CH3 (C~2)3 C6H5 lOl (CHz)6coo(n-c6Hl3) CH3 (CH2)8 C~H5 l (CH2)4COO(n-C4Hg) CH3 C(CH3)2(CH2)6 H
l (CH2)6COOC2H5 CH3 (CH2)30(c~2)4 H
2 (CH2)3C00C2H5 C~I3 OCH(CH3)(CH2)3 C6~5 (C 2)5COOCH3 . CH3 ( 3)2(CH2)6 H
2 (CH2)4cOO(i-c3H7) CH3 CH(CH3~(CH2)3 4-pyridyl (C 2)4COOC2H5 CH3 O~CH2)7 H
2 (CH2)COOCH3 C~3 ~H(C~I3)(CH2)3 4-FC6~4 The 3-[2-benzyloxy-4-~Z-W)phenyl]-4-(and 5)-~-(oxoalkyl)cycloalkanols of Examples 17, 64, 68 and 104 are converted to corresponding 3-[2-hydroxy-4-(Z-W)-S phenyl]-4-(and 5)-~-(carbamoylalkyl)cycloalkanols by the procedures of Examples 20 and 21 using, of course, the appropriate caxbamoylal~ylene triphenylphosphorane as the Wittiy reagent.
OH
(~ o Ry ~ Z-W
.~
s Rx Ry Z W
,,, ~
1 ~CH2)2cNH2 H ~CH2)7 H
l (CH2)2CONH(C2H5) H ctcH3)2(cH2)6 H
(C 2)3CONH2 H [CH(CH3)]2(CX2)5 H
( 2)3 2 (CH2)11 H
l (CE~2)5CON~CH3)2 H C(C~3)2(C~2)6 H
1 (CH2)2CON(CH3)2 H C(CH3)2(CE12)6 H
1 (CE~2)3~ONH2 H C(CH3)2(CH2)6 H
1 (CH~)2cNH2 H (CH2)11 H
1 (C~2)4cNH2 C(CH3)2(CH2)6 l (C~2)~CONH(C2~15~ H (CH2)8 H
l (CH2)6CONH2 H [C (CH3)2~2(cEI2)5 H
l (C~2)2CONH2 H (CH2)4 C6~5 l (CE~2)2CONH(C2H5) E (CH2)4 C6H5 (CH2)2cON~H3~2 H CH(CH3)(C~2)3 C~H5 8 i~
S RX Ry Z W
2) 2 2 CH (CH3) (CH2) 3 4--FC6H4 (C~2) "~CONH2 X CH(CH3) (CH2) 44-pyridyl 2 (CH2) 2CONH2 H CH (CH3) (CH2) 3 C6H5 2 ( 2) 3 H2 H C~ (C2~5) (CE~) 4 4--FC6H4 2 (CH2) 6CONH2 H C (C~3) 2 (CH2) 6 H
2 (CH2) 4CON(CH3) ~ H (CH2) 7 H
2 (CHz)3CON(CH3)2 H OcH(cH3) (CH2)3 C~HS
2 (CH2) 3CC)N~I (C2H5) H O H (CH3) (CH2) 3 4 C6H4 1() 2 (CH2) 6C~H2 H (CH2) 30CH(CH3)4-ClC6H4 2 (CH2)4CON(CH3)2 H O(CH~)7 (CH2) 3CONH2 E~ O (CH2) 4 C6~5 (CH2)6CONH2 H OCH(CH3) (CH;~)3 4-pyridyl (CH2) 6CON(CH3) 2 H [CH (C~I3) ] 2 (CH2) 5 H
lS 1 (CH2) 2CON(CE~3) 2 H (CH2) 4 C6H5 (CH2) 2CONH2 CH ( 3) (CH2~ 3C6H5 (CH2)6CONH2 H CH(C~I3) (CH2)3C~H5 (CH2) 2CONH2 H CH (CH3) (CH2) 3 2-pyxidyl (CH2)2cON(cH3)2 H [CH(C~3)]2CH2 4-pyridyl 2 (CH2)5CONICH3)2 ~ CH(CH3) (CH2)3 C6~5 I2) 3CON~I2 ~ C (C~3) 2 (CH2) 6 H
2 (CEI2) 3CON~I (C2H5) ~I C (CH3) 2 (CH2) 6 H
2 (C~2)3CONH;~ E )cH(cH3) (C~I2)3 C6Hs 2 (CH2) 4CONH2 ~ OCH (CH3) (C~I2) 3 C6~5 7.~ 4 2 ( 2) 6~ 6H5 2 (C~2) 3CONH2 H OCH (CH3~ (CH2) 5 EI
2 (C~l~) 6CON~2 H (C~I2) 11 H
(C~[2)3CONH(C2H5) H ( 3) (CH2)3 C6H5 (CH2) 4CN~2 ~ (CH2) 30CH (CH3) 2-pyridyl 1 (CH2)3cON(cH3)2 O~CH2)5 3-pyridyl 1 4 ~) ~
. ~
s RY Ry Z W
. . . _ H (2)2CON(CH3)2 C(CH3)2(CH2)6 H
H (H2) 3CONH (C2H5) C (CE~3) 2 (CH2) 6 B
2 H (2) 3CONH2 (CH2) 3O (CX2) 4 H
2 EI (2) 3CONH2 ( 3) 2 (l:~H2) 6 H
H (CH~)3CON(CH3)2 OCH(CH3; (CE~2) 6 5 H (C 2) 2CNH2 C (CH3) 2 (~H2) 6 2 EI ( 2) 3CN~2 (CH2) 5 H
2 ( 2) 3CONH2 (C~2) 11 H
2 H (CH~)3cON~cH3~2 OC~(CH3) (CH2)S H
2 EI (2) 3CONH2 C~I (CH3) (CH2) 3 C6H5 2 H (2) 3CONH2 CH (C2H5) (CH;~) 4 4-FC6H4 (CH2)2CONH2 CH3 C(CH3)2(CH2)6 H
( CH2 ) 2CO~-lS ( 3) 2 CH3 ( 3) 2 (CH2~ 6 H
( C~;2 ) 3CO~H2 CH OCH ( CH3 ) ( CH2 ) 3 C 6EI5 ~CH2)2CONH-(C2H5) CH3 OCH(CH3) (CH2)3 C6H5 t CH2 ) 2CON ~ .
~CEI3) (n-C,~H9) CH3 0CH(CH3) (CH2)3 ~ 6~5 (CH2) 4COWH2 CH3 (CH2) 7 H
2) 3CON-3H7) 2 C~3 (C 2)13 H
(CH2)2CONH~ . -6H13) CH3 CX (CH3) (CE[2) 3 4 FC6H4 2) 2CN
~n C4H~)2 CH3 CH(C~3) (CH2)3 4-pyridyl ~C 2)2CONEI2 CH3 OC~I(CH3) (CH2)3 C6H5 2 ( CH2 ) 3 CON~
(CH3) (n-C~Hg) C~3 0CH(CH3) (CH2)3 ~6HS
2 (CE~2) 5CON--(C2E~S) 2 CH3 ( 3) 2 (CX2) 6 $1~
--123 _ ,. _ .~ . . _ . _ _ ~ _ _ s Rx Ry Z W
. . . ~
2 (CH2)2CON(CE~3)2 CH3 C(CH3) (CH2)3 4-pyridyl 2 (CH2)4CONH(C2H5) C 3 O(CH2)7 H
(CH2) 3CONH
( i -C3H7 ) CH3 CH ( CH3 ) ( CH2 ) 3 4--FC ~; H4 2 ~CE~2) 3CONX-(n C6Hl3) CH3 C (CH3) 2 (CH2~ 6 H
Reduction of the above-listed amides accorrling to 10 the procedure of Example 23 a~ords the corresponding amines .
EXAMPLE 7l The 3-L2-hydroxy-4-(z-w)phenyl]-4~(or 5~-substi-tut~d-cycloalkanones and the 3-[2-benzyloxy-4-(Z-W~-phenyll-4-(or 5)-substituted-cycloalkanones wherain the suhstituent is other than ~-oxoalkyl of Examples 6, 8, 28, 53, 5~, 60, 63 and 65 a~e converted to corresponding cycloalkanes by the procedure of Example 250 The compounds have the formula shown below wherein ~ is hydrogen or benzyl, s, Z, W and the ~-(or 5) substituents are a~ defined in said examples ~ o (~s l OR
Rx ~ Z-W
EXA~IPLE 72 Following the procedures of Examples 26 and 5, the 3-[2-benzyloxy-4-(Z-W)phenyl]-4-(or 5)-alkenyl cyclo-alkanols of Examples 2, 13 r 15 ~ 29, 5G ar.d 61 are con-verted to the corresponding benzyloxycycloalkanols accvrding to the proc~dure of Example 26 a~d the ethers then hydrated by the p.rocedure of Example 5 to give the.
corresponding 3-t2-benzYloxY-4-(Z-w)phenyl~-4-(or 5)- 0 t~~hydroxyalkyl)-l-benzyloxycycloalkanes.
The 3-[2-benzyloxy-4-(Z-W)phenyl] 4-(or 5)~
hydroxyalkyl)-l-benzyloxycycloalkanes o~ Example 72 are converted to corrasponding ~-(Cl 6alkoxy1alkyl ethers ~5 by the procedures of Examples 26 or 27.
4 ~ ~
The 3-[2-benzyloxy-4-(Z-W)phenyl]-4-(or 5)-~(al~oxyalkyl)~l-benzyloxycycloalkanes of Examples 27 and 73 are debenzylated to the corresponding 3-[2-hydroxy-4 (Z-W)phenyl3-4-~or 5)-w-(alkoxyalkyl)cycloalkanols by the procPdure of Example 6.
Using the procedures of Examples 32 and 33, the cycloalkanol compounds of Examples 61, 67 and 70 are l~ converted to corresponding 3-[2-benæyloxy-4-(Z-W)phenyl]
~-(or 5)-substi-tuted-1-aminocycloalkanes.
Acetylation of the amino compounds thus produced provides the corresponding l-acetamidocycloalkanes. Of couxse, when more than one amino group is present, as in the 3-[Z-benzyloxy-4-(Z-W)phenyl]~4-~or 5)-~-(amino alXyl)-l-aminocycloalkanes, 2 molar proportions of each of acetic anhydride and 4-N,N-dimethylaminopyridine are used.
The compounds are de~enzylated to corresponding phenoLs by the procedure of Example 6 EX~MPLE 76 Using the procedure o~ Example S, the 3-[2-benzyloxy-~-(Z-W)~henyl~-4-lor S)-alkenyl-l-acetamidocycloalkan~s of Example 75 are hydrated to corresponding ~-hydroxy-al~yl-l-acetamidocycloalkanes.
Debenzylation via the procedure of Example 6 a~fords ~he c~r~espondin~ phenol derivatives.
t :~ 8 ~
EX~MPLE 77 Tra~s-3-(2,4-Dibenzyloxyphenyl)-4-(2-propenyl)cyclohexanone Using the procedure of Example 1, 23 g. ~62.3 mmole) o~ 2,4-dibenzyloxybromobenzene and 7.2 g. (53 mmole) of ~I-(2~-propenyl~-2-cyclohexanone gave 8.56 g. (38%) of the title compound.
m.p~ 104-106 C. (diisopropyl ether) HRMS (m/e) 426.2203 ~M , calc'd. for C29H3003:
426.218t~, 335, 181 and 91.
Analysis: Calc'd~ for C29H30O3 C, 81.66; H, 7.09.
Found: C, 81.53; H, 6.85.
Trans 3-(2,4~Dibenzyloxyphenyl)-4-(2-propenyl)cyclohexane ethylene Ketal A mixture of 5.0 g. (11.73 mmole) of trans-3-(2,4-dibenzyLoxyphen~ 4~(2-propenyl~cyclohexanone, 6.5 ml.
(117 ~mole) o~ ~thylene glycol and 223 mg. (L.17 mmole) of ~-toluenesulfonic acid in 50 ml. of benzene was heated at re~lu~ for 1.5 hours. Wate.r was removed via a soxhlet ex~ractor filled with molecular ~ieves. The reaction was cooled and added to 500 ml. saturated sodium bica.rbonate and 300 ml. ether. The ether phase was ~5 sepa.rated, dried over magnesium sulfate and e.vaporated.
Trituration with diisopropyl ether-hexane gave 5.31 g.
t96%) o~ ~he title compound.
m.p. 112-113 C.
HRMS (m~e) 470.2520 ~M , calc'd. for C31H34O4:
470.2448), 387, 379, 303, 181 and 91.
Analysis: Calc'd. for C31H34O4 C, 79.12; ~, 7.28.
Found: C, 79.13; H, 7.02.
~ ~81~4 -127_ Tr~ns-3-(2,4-Dibenzyloxyphenyl)-4-(3-hydroxypropyl)cyclohexanone ethylene Ketal Using the procPdure of Example 5, 5~00 g. ~10.6 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-~2-propenyl)-cyclohexanone ethylene ketal afforded a quantitative yield of the title compound as an oil. The product was used in the procedure o Example 80 without puriication.
10Trans-3-(2,4-Di.benzyioxyphenyl)-4-(3-hydrox~propyl)cyclohexanone A mixture of 5.17 g. (10.6 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-(3-hydroxypropyl)cyclohexanon~
ethylene ketal~ 50 ml. lN hydrochloric acid and 100 ml.
lS tetrahydrofuran was heated at reflux for one hour. The reaction was cooled, par-tially evaporated on a rotovapor ancl the residue diluted with 300 ml~ saturated sodium chloride-300 ml. ethex. The ether extract was washed with ~00 ml. saturated sodium bicar~onate, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ethex to yield 4.3~ g.
(92%) of the title compound.
m.p~ 110~117 C.
Anal~sis: Calc'dO Eor C29H320~:
2S C, 78.35; H, 7.26.
_und:C, 78.17; H, 7.15.
Trans -3 - ( 2, 4 -Dihydroxyphenyl ) - 4-(3 hydroxypropyl)cyclohexanone Fol~o~ing the procedure of Example 6, 3.9 g.
(8.7~ mmole) of trans 3-(2,4-dibenzyloxyphenyl)-4-(3 hydroxyphenyl)cyclohexanone provided 2~12 gO (91%) of the title compound as an oil~
HRMS (m/e) 264.1345 (M , calc'd. for C15H20O4:
264.1356), 178, 163, 161, 155, 136 and 123.
- \
-128_ -3r 4-Dihydro-2-me~hoxy~7-hydroxy-2,4-proparlo-2~-1-beIlzopyran-9-proPanol _ A solution o~ 1.5 g. (5.68 mmole) of trans-3-(2,~L-dihydroxyphenyl)-4-(3-hydroxypropyl~cyGlohexanone in ~0 ml. methanol, 6 ml. trimethylorthoformate and 7 drops of concentrated sulfuric acid was stirxed at 0 C. for 45 minutes. The reaction was quenched by the addi tion of excess solid sodium bicarbonate and then evaporated on a rotovapor. The residue was dilutad with 300 ml. saturated sodium bicarbonate-300 ml. ether.
The ~ther ectract was dried over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 150 g. of silica gel eluted in 15 ml.
~ractions with ether to yield 1.29 g. (82~) of the title compound as an oil.
PMR ~CDC13 ~ D6-DMSO) ~ 1.88 tm), 2.85 (m), 3-35 (s, methox~), 3.45 (m, methylene), 6.22 (d, J=2~z, Ar~), 6.22 (dd~ J=8 & 2Hz, Ar~) and 6.75 (d~ J=8Hz, ArH).
HRMS (m/e) 278.1514 (M , calc'd. for C16H22O4:
~78.1512), 246, 192, 177 and 161.
~ ~8~4~
_129 _ d-3,~-Dlhydro-2-methoxy 7-~(2-octyl)oxy]-2,4-propano~2H-1 benzopyran-9-propanol _ ~ mixture of 700 mgO (2.52 mmole3 o~ 3,4-dihydro-2-methoxy-7-hydroxy-2,4-propano-2H-l-benzopyran~g~propanol 786 mg~ (3.78 mmole) of 1-2-octylmethanesulronate and 1.33 g. (10 mmole) o~ anhydrous potassium carbonate in S ml. of dimethylformamide was heated at 80 C. for 8 hours and then stirred at room temperature for 10 hours.
11) The reaction mixture was added to 300 ml. saturated sodium chloride-300 ml. ether. The ether extract was driPd over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 100 g.
oE silica gel eluted in 10 ml. fractions with ether to lS yield 711 mq. (72%) of the ti~le compound as an oil.
PMR (CDC13) ~ 0.88 (m, terminal ~ethyl), 1.28 (d, ~ æ, me~hyl), 2.95 (m), 3.40 (s, methoxy), 3.70 (m~
methylene), 4.22 (m~ methine), 6.35 (m, ArH) and 6.82 (d, J=8H2, Ar~).
EIRMS (m/e) 390. 2769 (M , calc'd. for C24H38O4:
390.2760), 304, 289, 273, 192, 191, 177 and 161.
ln~20 C~ = +3.17 (c = 1~29 methanol) d-Trans-3-[2-hydroxy-4-(2-octyloxy)phenyl~-4--_ _ (3-h~droxypropyl)c~clohexanane ~ mixture o~ 711 mg. (1.82 mmole) of d-3,4-d.ihydro-2-me thoxy-7- ~ ( 2-octyl)oxy]-2,4-propano-2H-l-benzo~
pyran~9-propanol, 25 ml. tetrahydrofuran and 15 ml. lN
hyd~ochl~ric acid was heated 1.5 hours at reflux. The reaction was cooled and diluted with 200 ml. sa~urated sodium chloride-200 ml. ether. The ether e~trac~ was washed with 200 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to give a quanti~
tative yield or the title compound as an oil.
HRMS (m~e) 376.2592 (M , calc'd. for C23H360~:
376.~604), 290, 275, 264, 179, 178, 177, 164, 163 and 161.
_130-~X~MPL~ a s d-Cis-3-~2-hyd~oxy-4-(2-octyloxy)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol and the trans-3, CiS-4 isomer _ _ _ Using the procedure of Example 2, 684 mg. (1.82 mmole) of d-trans-3 ~2-hydroxy-4-(2-octyloxy)phenyl]-4-(3-hydroxypropyl)c~clohexanone yielded in order of elution with 50~ ether-dichloromethane, 420 mg. t61~) of the title compound and 75 mg~ j of the trans-3, C15-4 isomer as oils.
10 . Cis~3, trans-~
[a]20 C- = ~4.26 (c = 1.01, methanol) EIRMS (m/e) 378.2762 (M , calc'd~ for C23~3~0~:
373.2760), 266, 2~18, 147 and 123.
Trans~3, cis-~L
H~MS (m/e) 378.2789 (M , calcld. for C23H38O4:
378.2760), ~66, 248 and 123.
The compounds tabulated below are prepared according to the procedures of Examples 83 and 84 ~rom the appro~
priate reactant CH3 SO2-O-Z-W.
~H
(~1~o (alk2)-W
CH~OH
2 ) w (CH~)4 C6~5 CH(CH3~c~2)3 C6H5 CH(CH3)(c~2)5 C6H5 ~ 131 ~
(alk2 ) W
C~I5CH3) (CX2) 3 4--ClC6~4 C~l~C~3) (C~2) 3 4-FC~jH4 CH (CEI3 ) (CH2 ~ 5 H
(CH2~ 11 El CH(C~3) (CH2) 3 4-pyridyl ( C~I2 ) 4 2-pyridyl (CH2) 72-pyridyl 2) 13 H
(CH2) 3 C 6 5 I ~$~
-132_ 1-3~4-Dihydro-2~methoxy-7-L(2-octyl)oxy3 2,4-propano-2H--l-benzopyran-9-propanol Using the procedure of Example 83, 700 mg~ (2.52 mmole) of 3,4~dihydro-2~methoxy-7-hydroxy-2,4-propano-2H-l-~enzopyran-9~propanol and 786 mg. (3.78 mmole) of d-2-octylmethanesulfonate gave 742 mg. (75%) of the title compo~md as an oil.
PMR (CDC13) ~ 0u88 (m, methyl), 1.29 (d, J-6Hz, methyl), 2.g2 (m, methine), 3,38 (s, methoxy), 3.7 (m, methylene), 4.25 (m, methine), 6.3 (m, Ar~) and 6.80 ~d, ~=8EIz, ArH).
~a320 = 1.76 (c = 1.33, methanol) H~MS (m/e) 390.2763 (M , calc'd. for C24H38O4 390.2769), 304, 289, 278, 273, 246, 192, 191, 177 and EX~MPLE 87 l-Trans 3-[2-hydroxy-4-(2-octyloxy)phenyl]-4-= (3-hydroxypropyl)cyclohexanone Using the procedure o~ Example 84, 742 mg. ~1,90 m~lole) o 1-3,4-dihydro-2-methoxy-7-[(2-octyl)oxy~-2,-l-propano-2H-l-~enzopyran-9-propanol ga~e a quantitative yiel~ of title compou~d as an oil.
HRMS (mfe) 376.2624 (M+, calc'd. for C23~I360~:
376.2592), 264, 179, 178 and 177.
4 ~I L~
~133-l-Cis-3- r 2-hydroxy-4-(2-octyloxy)phenyl]-trans-4-(3-hydroxyprop~l)cyclohexanol and the trans-3,cis-4 isomer Using the procedure of Example 5, 714 mg. (1.90 S mmole) of l-trans-3~~2 hydroxy-4-(2-octyloxy)phenyl~-4-(3-hydro~Yypropyl)cyclohexanone afforded 483 mg. (67%) of the title compound and lDl mg~ ~14~ of ~hg tr ns-~5 CiS-'i isomer as oils.
Cis~3, trans-4 ~ O C = -5,214 (c = 1.13, methanol) HRMS (m/e) 378~2775 (M~, calc'd~ for C23H3~O4:
378.2760), 26G, 249, 248, 147 and 123.
?ranS-3, CiS-4 _ __ HRMS (m/e) 378.2767 (M+, calc'd. for C23H38O4.
378.2760), 266, 248, 189, 149, 147 and 123.
Followlng the ~rocedures of Examples 77 - 81, 4-(2-propenyl~-2-cycloheptenone is converted to trans-3~(2,4-dihydroxyphenyl)-4-(3-hydroxypxopyl)cyclo-heptanone.
- ~ \
~ ~ 1 4 ~ L~
-.134-Repetition o~ the procedures of Examples 82 - 88, but using trans-3-~2,4-dihydroxyphenyl)-4-(3-hydroxy-propyl)cyclvheptanone as reactant in Example 82 proc~dure, and the appropriate CH3S02-0-Z-W alkylating agent affords the following compounds:
~H
(~ fH
~0- (alk2)-W
(alX2 ) W
C~l (CH3 ) ~CH;l! ) 6 H
CH(C~3)(CH2)5 H
(CH2)11 N
C~(CH3)(CH~)3 C6HS
(C~2)4 C6HS
C~(CH3)(C~2)3 4-FC6H4 (CH2)4 4-pyridyl !135-Trans-4-[2-Propenyl)-3-[2-(tetrahydropyranyl-2-oxy~-4~(1,1-dimethyL)-cis-2-he~tenyl)phenyl]cyclohexanone _ . . . ~ ~
To a 0C. solution of 2.0 g. (6.62 mmole) of 1,1-dimethyl-1-[3-(tetrahydrop~ranyl-2-oxy)phenyl3 -cis-2-hepta~e and 84~ mg. t7~28 mmole) of tetramethylethylene diamine in 10 ml~ of ether was slowly added 3.17 ml.
(7.28 mmole~ of n-butyllithium (in hexane). The resultant solution was stirxed 5 minutes at 0C. and then refluxed for 70 minutes. The xesultant was then cooled to -78C.
To a ~C. solution of 597 mg. (7.28 mmole) of 1-he.Yyne in 10 mlO of tetrahydr~furan is slowly added 3.L7 ml. (7.28 mmole) of m-butyllithium (in hexane).
The resultant solution was stirred 10 minutes at 0C.
and then slowly added to a 0C. slurry of 1.38 g.
(7.28 mmole~ of cuprous iodide in 10 ml. of tetra-hydrofuran. The resultant yellow slurry was stixred 30 minutes at 0C. and then slowly added to the above prepared -7~C~ solution of ar~l lithium reagent. The resultant ye~low mixture was stirred 10 minutes at -7~'C. and then 900 mg. (6.62 ~mole) of 4-(2-propenyL)-cyclohe:c-2-en-1-one is added dropwise~ Stirring was continued for 10 minutes and then the reaction was placed in a -~O~'C. cooling bath and allowed ~o warm to -2q~. over 20 minutes. The reaction was quenched by addition to 200 ml. of cold saturated ammonium chloride ~rought to pH 10 with saturated ammonium hy-droxide. The quenched reaction mi~ture was ext~~acted with 300 ml. of ether. The ether extrac~ was dried ~ver magnesium sulfate and eva~orated to an oil which was purlfied via column chrcmatogra~hy on 200 g. of silica gel eluted in 15 ml. 'ractions wit~ 0~ ethe-~hexane to ~ield ~-om _rac. cns ~0-63, 2.36 g. (82~) of the ti~le ccmpo~nd as an oil.
-,:
n ~
E,YAMPLE 91 (Cont.) I~ (C~C13) 1709, 1641, 1610 and 1571 cm 1, HRMS (m/e) 354.2569 (P. -C5H80: Calcd. for C24H32O2:
354~2550), 272, 271, 161, 137 and 85 (100~.
P~R tCDCl~) ~ 0.69 (m, terminal CH3), 1.41 (s, gem dimethyl), 0.8-4.2 (series of m), 4.7-5.6 (m, olefinic H and THP methine), 5.62 (d, J=12Hz, vinyl H) and 6.7-7.3 (m, ArH).
Trans-4-(2-Propenyl)-cis-3-[2-(tetrahydropyranyl-2-o~y)~ dimethyl-cis 2-hQptenyl)phenyl]-cyclohexanol and the cls-4,trans-3 isomer ~'o a -78C~ ~olution of 20~0 g. (45.7 mmole) of trans-4-(2-propenyl)-3-f2-(te$rahydr~pyr2nyl-~-oxy)~~-__ ~l,l-dimethyl-cis-2-heptenyl)phenyl]cyclohexanol in 200 ml. of me~hanol was added in one portion 5.20 g.
(137 l~mole~ Oe sodium borohydride. The reaction was stirxed overnight at ~78C. and then allowed to warm to ODC. The reaction was quenched with 10 ml. satu-rated sodium chloride and then concentrated on a rotova~or. The residue was diluted with S00 ml.
saturated sodium chLoride and 500 ml. ether. The et.her extract was washed once with 250 ml. saturated s~dium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 1 kg. of silica gel eluted with 3a~ ether~hexane to yield in order of elution 2.20 g~ ) of the cis-4, trans-3 isomer, 0.74 g.
(4%) of mixture ~nd 17.0 g. (S5%) of the title compound as oils.
~itle Compound:
IR (CHC13) 3593, 3464, 1640, 1610 and 1571 cm 1.
HRMS (m/e) 3S6.2709 (P. -C5H8O, Calcd. for C2~H36O2:
356.2706), 297, 273, 255, 124 and 8S (100%).
P~IR (CDC13) ~ 0.70 (m, terminal CH3), 1.42 (s, gem dimethyl), 2.8 (bm, benzylic methine), 3.4 4.1 (m, carbinol methine and OCH2), 4.6-5.5 (m, vinyl H and THP me~hine), 5.60 (d, J=L
Hz, ~iny; H) and 6.8-7.2 (m, ArH).
-138 ~
XAMPLE ~3 Trans-4-t3~ droxypropyl)-c 3-[2-(tetrahydro-pyranyl-2-oxy)-~(1,1-dimethy.l cls-2-heptenyl~
phenyl]cyclohexa~ol To a -54C. solution of 13.3 g. (0.0302 mole) of rans-4-(2 pxop~nyl)-ClS-3-[ 2-(tetrahydropyranyl-2-oxy)-4-(1,1-di~lethyl-cis-2-~eptenyl)p~ny~3cyclDne~anoi in 100 ml. of tetxahydrofuran was slowly added 35.1 ml.
(0.0351 mole) o boran-tetrahydrofuran (lM in tetxa-hydrofuran), wi~h stirring. After 30 minutes another 50 ml. of tetrahydrofuran was added and ~he reac~ion stirred 30 minutes longer, then quenched by addition of 40 ml. ~0.12 mole) of 3N sodium hydroxide and oxidized hy addition of 10 ml. (0.112 mole) o~ 30% hydrogen peroxide. After stirring 20 minukPs the reaction was added to 50Q ml. saturated sodium chloride - ~00 ml.
ether. The aqueous phase was extxacted with another 2 5 0 ~1 . portion of ether and the combined ether extract dried over magnesium sulfate and evapoxated to an oil. Th~ cru~e oil was puri~ied via column chroma-tography on 1 ~g. of silica gel eluted with 80% ether-hexane to 3~ methanol-ether to yield in ~rder of elution .
600 mg. (5%) of unreacted starting material, 7O45 g.
(54%~ of the title compound as a~ oil, 1.3~ g. (12%) of trans-4-(3 ~ydro~cypropyl) -ClS-3 - ~2-hydroxy-4-(1,1-di-methyl-cis-~-heptenyl~phenyl]cyclohexanol (phenolic product) and 1.7B g. tl3%) of trans-4-(3-hydroxy propyl)-cis-3-[2-ttetxahydropyranyl-2-oxy)-4-(1,1-dimethyl-3-hydroxyheptyl)phenyl]cyclohexanol ( Triol -THP).
~ .~ 8 ~
--139 _ Example 93 (Cont ) Ti tle Compound:
HRMS (m/e~ 874.2a31 (P. -C5H80, Calcd. for C24H3803:
37'1.2811), 356~ 242, 151 and 85.
PMR(CDC13) C 0.72 (m, terminal CH3), 1.40 (s, gem dimethyl) ~ 2.,8 (m, benzylic methine), 3.47 (m, CH2OH), 3 ~ 2-4 . 2 (m, car~inol methine and -CEI20-), 4 . 9-S . 5 (vinyl H and THP methine), 5 . 62 (d, J=llHz, vinyl H) and 6 . 9-7 . 2 (m, ArH).
10 Pheno tic Pxoduct:
~lS (m/e) 374.2839 (M+, Cal::d. for C24H3803:
37~.2811) r 356, 341, 299~ 273 and ~70.
Triol-T~IP:
HRMS (m/e) 392 . 2949 (P. -C5~80, Calcd. for C24H4004:
392.2916), 374, 292, 274, 165 a~d 85 (100~).
4 ~ ~
1~0 .
~XAMPLE 9~
Trans-4-(3-d-Mandeloyloxy)-c1s-3-[2-hydroxy-4-(l,l~dLmethyl~cis-2-heptenyl)phenyl]-1-d-mandeloyloxy-cYclohexane A mixture of 6.00 g. (13.1 mmole) of trans-4-(3-hydrQXyprOpyl) -CiS-3- [2-(tetrahydropyranyl-2-oxy)-4-(l,l-dimethyl-cis-2-heptenyl)phenyl]cycloh xanol, 9.96 g. (6S.5 mmole) d-mandelic acid and 498 mg.
2.62 mmole) p-toluenesulfonic acid monohydrate in 250 ml~
of benzene was heated at reflux. Water was removed via a 3A molecular sieve filled soxhlet extractor. The xeaction was heated at reflux for 160 minutes wi~h additional portions of p-toluenesulfonic acid mono hydrate added at 40, 80 and 120 minutes. The reaction was cooled and added to 500 ml. saturated sodium bi-carbona~e - 500 ml~ ~ther. The aqueous phase was ex O
tracted with a second 250 ml. portion of ether and the combined ether extract dried over magnesium sulfate and av~porated to an oil. The crud~ product w~s purified vi~ column chromatography on 800 g. of silica gel eluted wit~ 55% e~her-hexane to yield order o~ elution 2.25 g.
(2~) o~ diastereomer A of the title compound, 20 0 g.
(24~) of a mixtu~e and 4.0 g. (48~) of slightly impur~
diastereomer B o the title compound as ~ils.
Dias~reomer A:
20~ ]CEt3o~ = + 31.62 (C=1.85) P~R ~CDC13) ~ 0.68 (m, terminal CH3), 1.37 (s, gem dimathyl), 3.4 (bd, J-6Hz, OH), 3.93 (bt, J=
6Hz, -CH2O-), 4.75 (m, OH), 5.02 (m, C OH), 5.0-5.7 (m~ vinyl H), 6.6-6.9 (m, ArH~, 7.23 and 7.26 (s, PhH).
., 4~)~
-141_ EX~MPLE 95 Trans-4-(3-hydroxypropyl)-cis-3-[2-hydroxy-4-(l,l-dimethyl-cis-2-heptenyl)phenyl]cycloh xanol . _ . . . . _ A mixture of 3.10 g. (4.82 ~mole) of diastereomex 5 A of trans~4- (3-d-mandeloyloxy) -cis-3 - [2-hydxoxy-4-(l,l-dimethyl-cis-2-heptenyl)phenyl]-1-d-mandeloyloxy-cyclohexane, 5,3~ g. ~38.6 mmoLe3 potassi~n carbona~e~
40 ml. methan~l, 40 mlO tetrahydrofuran and 10 ml. water was s~irred at Z5~C. for 24 hours. The reaction was evapoxated on a rotovapor and the residue dissolv~d in 250 ml. ether - 250 ml~ saturated sodium chloride. The aqueous phase was ex-tracted with two additional 150 ml.
portions o~ ether, the combined ether extract dried over magnesium. sulfate and evaporated to an oil . The crude lS produc~ was purified via column chromatography on 150 g.
of silica gel eluted with ether to yield 1.3 g. (72%) of the title compound.
~P: 95-97C. (Diisopropyl ether-haxane) ~oo[~]CH30H = -56 32 ffRMS (m~e) 374.2319 (M~ , Calcd. for C24~3803:
37~.2811), 356, 213, 187; 16~ 7, 124, 121, and 93~
P~R (250 mH2, CDC13) ~ 0.73 ~m, te~ninal methyl), 1.39 (s, gem dimethyl), 2.03 tm, CH2 vinylic), 2.72 (m, benzylic methine), 3.47 (m, CH~OH), 3~7~ (m, CHOH), 5.07 (bs, OH), 5.22 and 5.27 (dt, J=11.51 and 7.31 Hz, vinyl H), 5.61 (dt, J=ll.Sl and 1.6 Hz, vinyl H3, 6.73 (d, J=1.64 Hz, ArH), 6.91 (dd, J=8.22 and 1.8~ Hz, ArH) and 7.02 (d, J=8.04 Hz, ArH).
~XAMPLE 96 T.ans 4-(3~hydroxypropyl)-cis-3-[2-hydroxy-4-(l,l-dimethylheptyl)phenyl]c clohexanol ~ mixture of 50.0 mg. (0.134 mmole) of (-)-trans-5 4-(3~hydroxypropyl)-cis-3-[2-hydroxy-4-(1,1-dimethyl-ci ~-heptenyl)phenyl]cyclohexanol and 50 mg. of 10~
palladium on ca.rbon in 5 ml. of dry tetrahydrDf~7r_n was stirred under one abmosphere of hydrogen for 30 minutes.
The reaction was filtered through diatomaceous earth L0 with te~rahydrofuran and the filtrate evaporated to ~ield 47.9 mg. (95%) of the title compouIld as an oil.
20[~]DH3H = -36 12 .
~ 3_ Trans-3,4,trans-4,5-3-[2-benzyloxy-4~ dlmethyl-heptyl)phenyl]-5-methyl-4-(2-propenyl ? cyclohexanone . _ Using the procedure of Example l, 7.5 g. (50 mmole) S Of trans-5-methyl-~-(2-propenyl)cyclohex-2-en-l-one and 2~1.3 g. (62.5 mmole) of l-benzyloxy-2-bromo-5-(l,l-di-meth~lheptyl~benzene gave 13.0 g. ~57~ of the title compound as an oil.
IR (CHCl3) 1709, 1639, 1609 and 1568 cm l, HRMS (m/e) 460.3353 ~M+ , Calcd. for C32H44O2:
460.3330), 375, 370, 369 and 9l (lO0~).
PMR (CDCl3) ~ 0.82 (m, terminal CH3), 1.26 (s, gem, dimethyl), 4.5-5.1 (m, vinyl H), 5.00 (s, benzylmethylane), 5.3-5.8 (vinyl H), 6.6~7.l (m, ArH) and 7.25 (bs, PhH).
In like manner, trans-3~4-trans-4,5-3-[2-benzyloxy-4~ ( 1, 1 -dimethylheptyl ) phenyl]-5-methyl-4 (2-propenyl)-cycloheptanone is prepared from trans-5-methyl-4-(2-prop~nyl)cyclohept-2-en-l-~ne.
~ ~8~
-1~4 -Cis-3-L2-benzyloxy-4-(1,1-dimethylheptyl)phenyl] CiS-5-methyl-trans-4-(2-propenyl)cyclohexanol _ _ _ . . . _ . .
Using the procedure of Example 2, 6.0 gO (13.0 mmole3 of trans-3,4-trans, 4,5-3-[2-benzyloxy~4-(1,1-dimethylhep-tyl)phenyl]-S-methyl-4-(2--propenyl)cyclohex-anone gave 1.1 g. (18~ o~ the cls-~,trans-3,trans-~
isomer of the ~itle compound, 1.077 g. (17%) of a mi~-ture and 2.79 (46%) of the title compound as an oil.
Cis-~,Trans-3,Trans-5 Isomer-HRMS (m/e) 462.3501 (M. F Calcd. for C32H4602:
362.3486)~ 377, 269, 227 and 91 (100~).
PMR (CDC13) ~ 0.82 (m, terminal methyl), 0.95 (d~
J=6Hz, methyl), 1.23 (s, gem dimethyl), 3.5 lS (m, benzylic methine) r 4.13 (m, carbirlol . methine~, 4.6-5.0 (m~ vinyl H), 5.05 (s, benzylic methylene), 5.2 6.1 (m, vinyl H), 6.35 (mr ArH~, 7.05 (d~ J=8Hz, ArH~ and 7.3 (bs, PhH).
20 Title Compound: .
IR (CHC13) 3596, 3463, 1~39, 1609 and 1570 cm 1.
H~MS (m/e) 462.3499 (M. , Calcd. for C32H460~:
'~62.3501), 377, 353, 269, 227 and 91 (100~).
P~R (CDC13) ~ 0.83, (m, terminal C~3), 1.25 (s, gem dimethyl~, 3.2 (m, benzylic methine), 3.62 (bm, arbinol methine), 405-5.0 (m, vinyl H), 5.02 (s, benæyl~c methylene), 5.3-6.1 (m, vinyl H), 6.82 (m, ArH), 7.00 (d, J=
3HZr Ar~) and 7.35 (bs, Ph~).
~ollowing the above procedure trans-3,4-trans-4,5-3~[2~benz~10xy-4-(l,l-dimethylhep~yl)phenyl~-5-methyl-trans-4-(2-propenyl)cycloheptanone is prepared from the correspondingly substituted cyclohept-2-en-1-one.
4 ~
Trans-3,4-Trans,4,5-3-~2-benzyloxy-4-(1,1-dimethyl-hep~yl)phenyl]-5-methyl-4-(2-propenyl)cyclo-hexanone ethylene ketal A mixture of 7~0 g~ (15.2 mmole) of trans-3,4-trans,~l,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~
~-methyl-4-~2 propenyl~cyclohexanone/ 8.47 ml. ~152 mmole) of e-thylene glycol and 289 mg~ (1.52 ~mole) of ~-~oluenesulfonic acid monohydrate was heated at reflux for 2.5 hours~ Water was removed via a soxhlet extractor Eilled with 3A sieves. The reaction was cooled and added to 250 ml. saturated sodium bicarbonate - 250 ml. ether.
The ether extract was dried over magnesium sulfate and evapora~ed to an oil. The crude product was purified via column chromatography on 300 g. of silica gel eluted with 20~ ether-hexane to yield 5.2 g. (68~) o~ the title compound a~ an oil.
IR (CHC13) 163~, 1608 and 1569 cm 1 ÇIRMS ~m/e) 504.3579 t~. , Calcd. for C34H480 50~.3591), 419, 413, 407 and 91 (100~).
PMR ~CDC13) ~ 0.82 (m, terminal methyl), 0.99 (d, J=6-~z, OEI3), 1.25 (s, gem dimethyl), 3.4 (m, benzylic methine), 3.90 (s, ethylene lcetal), 4.4-5.0 (m, ~inyl H), 5.03 (s, benzylic ~S methylene), 503-6.2 (m, vinyl H), 6.80 (m~
ArH), 7.00 (d, J-8Hz, ArH) and 7.35 (bs, PhH).
The ethyLene ketal o~ trans-3,4-trans-4,5-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl~4~(2-propen~l)cycloheptanone is prepared in liXe manner from the corresponding cycloheptanone~
_146-Cis-3-[4-(1,1-dimethylheptyl)~2-hydroxyphenyl]-.. . cis-5-methylcyclohexanol To a 0C. solution of 900 mg. (1.95 mmole) of CiS-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~ -5iS-5-methyl-trans-~-(2-propenyl)cyclohe~ancl in 2 ml~ of ether was added ~.1 ml. ~11.7 mmole) of n-butyllithium (in hexane). The reaction was stirred 10 hours at 25C. and then added to 200 ml. ether 200 ml. saturated ammonium chLoride. The ether extract was dried over magnesium sul.fate and evaporated to an oil. This oil was cxystal-lized in hexane to yield 495 mg. (68~ of the ~itl~
compound.
MP 149-150 QC. . (hexane) ~R (CHC13) 3455, 3253, 1643, 1617 and 1583 cm 1.
HRMS (m/e) 372.3050 (M. , Calcd. for C25HA 02:
. 372.3018), 312, 288, 287 (100%), 272, 269, 227, 187, 161, 147 and 135.
A ~ :
Analysis Calcd. For C25H~0O2~ C, 80.59; Hl 10.8~
Found ~ C, 80.35; H, 10.81 De~enzylation o~ cis-3-[2-benzyloxy-4-(1,1-dimethyl-heptyl.) phenyl]-cls-5-methyl-_rans-4-(2-propenyl)cyclo-heptanol is carried out in llke manner.
~814~
-1~7-Cis-3-C2-Benzyloxy 4-(1,1-dimethylheptyl)phenyl~-trans-4-(3-hydroxypropyl) -CiS 5-methylcyclohexanol _ . ~
Using the procedure of Example 5, 900 mg. (1.95 mmole) of cls-3-~2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl] cis-5-methyl-trans-4-(2~propenyl)cyclohexanol was converted in quantitative yield to the title com-pound, an oil.
H.RMS (m/e) 480.3574 (M. , Calcd. for C32~803:
480.3591), 462, 395, 377, 287 and 91 (100%).
By means of thls procedure, CiS-3- [2-benzyloxy-4-(l,l-dimethylh~ptyl)phenyl]-cis-5-methyl-trans-4 (2-propenyl)cycloheptanol is converted to the corresponding 3-h~droxypropyl derivativeO
n 4 -1~8 ~
Cis-3-~4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-4-(3-hydroxypropyl)-cis-5-methylcyclohexanol Using the procedure o~ Example 6, 936 mg. (1.95 mmole) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-~hen~13-trans-4~3-hydroxypropyl~-c~s-S-meihylcycio-hexanol afforded 602 mg. ~79%) of the title compound.
~P 159-160C. (diisopropyl ether - ethyl acetate) IR (ECBr) 3533, 3367, 3211, 1617 and 1585 cm 1.
E{.RMS (m/e) 390.3100 (M~ , CaLcd. for C25H4203, 390.3123), 372, 304, 288, 287, 272, 257, 227, 219 and 187.
nal~sis:
. C c . r C25H42O3: C, 76.87; H, 10.84.
LS Found : C, 76.60; H, 10.66.
Similarly, cis-3-[2-benzyloxy-4-(1,1-dimethyl-hept~l)phenyl]-trans-4-(3-hydroxypropyl)-cis-5-methyl-cycloheptanol is debenzylated to the corresponding phenol.
n 4 --1~19`--Trans-3,4 t Trans-4,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl) phenyl]-4-~2-hydroxypropyl)-5-methylcyclohexanone _ ethylene ketal - - _ S To a 25C. mixture o~ 3 28 g. (10.3 mmole) of mercuric acetate in 50 ml. of 50~ aqueous tetrahydro-~-~an wa~ added 5~2 g. (10.3 m~ole) ~f trans-3,4,t~ans-4,5-3-[-2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~-5-methyl-4-(2-propenyl)cyclohexanone ethylene ketal in 25 ml~ tetrahydrofuran. Another 25 Ial. of water was added to aid solution and stirring. Additional l.S g~
(4.7 mmole~ portions of mercuric acetate were added after 2 hours and 24 hours~ The reaction was stirred a total of G4 hours at 25C. and then xeduced by addition of 20 ml. 3N sodium hydroxide and 20 ml. of 0.5M sodium borohydride in 3N sodium hydroxide. The reaction was stirred 30 minutes longer and then added to 250 ml.
etner - 300 ml. saturated sodium chloride. The ether extract was dried over magnesium sulfate and evapora~ed to an oil. The crude produc~ was puri~ied Yia column chromatography on 300 g. of silica gel eluted with 50%
ether-hexane to give 1~5 g. (30%) of the title compound as an oil.
HRM~ (m/e) 522.3712 (M+ , Calcd. for C34HSoO~l:
527.. 3~96), 431, 407, 372, 113 and 91 (100%).
PMR (CDC13) ~ 0.75 (m, terminal methyl~, 0.92 (d, J=6Hz, C-5 methyl), 1.24 (s, gem dimethyl), 3.35 (bm, carbinol and benzylic methines) 7 3-90 tbs, ethylene ketal), 5.03 (s, benzylic methylene) and 6.6-7.5 (m, Ar~I).
Trans-3,4-trans-4,5-3-[2-benzyloxy 4~(1,1-dimethyl-heptyl)phenyl]-4=(2-hydroxypropyl)-5~methylcyclohepta-none ethylene ~etal is also prepared via this procedure from the corr~sponding 4-(2-propenyl)cycloheptanone ethylene ketal~
t ~ 4~
r _ Trans-3,4,Tran~-~,5-3-[2-Benzyloxy-4-(1,1-dimethyl-heptyl)phenyll-5-methyl-4-(2-oxopropyl~cyclo-hexanone ethylene ketal To a 25C. mixture of 1.5 g. (2.87 mmole) of trans-3,~,trans-4,5-3-[2-~enæyl.oxy-4-(1,1-dimethylheptyl)-phenyl]-~-~2-nydIoxypTopyl3-~-met~ylc~clo~x~n~
ethylene ketal and 2.35 g. (28.7 mmole) of sodium acetat~
in 20 ml. of dichloromethane was added 1.93 g. (9 mmole) LO of pyridinium chlorochromate. The reaction mixture was stirred 3 hours at 25C~ and then added to 250 ml. lN
NaOH-250 ml. ethex. The organic extract was dried over magnesium sulfate and evaporated to gi~e a quantitative yi.eld oE the title compound as an oil.
PMR (CDC13) ~ 0.85 (m, methyls), 1-.23 (s, gem dimethyl), 1.80 (bs, CH3CO-), 2.23 (bs, -CH2CO-), 3~3 (m, benzylic methine), 3.93 - (s, ethylene ketal), 5.05 (s, ~enzylic methylene) and 6.7-7.6 (m, ~r~).
In like manner, oxidation of trans-3,4-trans-4,5-3-~2-ben2yloxy-4-~l,1-dimethylheptyl)phenyl]-4-(2-hydrox~propyl)cyclo}leptanone ethylene ketal af~ords .the corresponding 4-(2~oxopropyl)cycloheptanone ethylene ketal.
~ .
~ ~ 8 ~
--15 1_ -Trans-3,4-Trans-~,5-3-[2-Benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)-cyclohexa~one ethylen~ ketal S To a 15C. mixture of 5 . 74 mmole of triphenyl phos-phoniummethylide in 6 ml. of dimethyl sulfoxide was added æolu~ion of 1.5 g. ~2.~7 ~mole) of t~h~-3,~-trans~,3-3-[2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-t2-oxopropyL)cyclohexan~ne ethylene ketal in 6 ml. of tetrahydrofuran and the reaction stirred 1.5 hours at 15-25C. It was then added to 200 ml. saturated sodium chloride - 200 ml. ether. The ether extract was washed once with 200 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated to give an oil. Puri fi~ation via column chromatography on 50 g. of silica gel eluted with 20~ ether-hexane gave 1.17 g. (79%~ of the title compound as an oil.
HRMS lm/e~ 518.3706 (M. , Calcd. for C35H50O3:
518.3747), 462, 427, 407, 372, 371, ~85 and 91 (100%).
PMR (CDC13~ ~ 1.25 (s, gem dimethyl~ 48 (bs, vinyl methyl), 3.3 (m, benzyllc methine), 3.89 (s, ethylene ketal), 4.40 (mt vinyl H~ t 5~02 ~s, benzylic methylene), 6.85 (m, ArH), 7.10 (d, J=8H~, ArH) and 7.4 (m, PhH).
Trans-3,4-trans-4,5-3-~2-bellzyloxy 4-(l,1-dimethyl-_ heptyl)phenyl~-5;methyl-4-(2-oxopropyl)cycloheptanone ethylene ~etal is converted in like manner to the corres-pondin~ 4~(2-methyl-2-propenyl)cycloheptanone ethylene ketal.
) 4 --15 2_ Trans-3,4-trans-4,5-3-[2-Benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)-_ _ cyclohexanone A mixture of 1.1 g. (2.12 mmole) of the ethylene Xetal of the title compound, 20 ml. tetrahydrouran and 20 ml. lN hydrochloric acid was heated at reflux for 5 hours and stirred at 25C. for 16 hours. The reaction was added to 250 ml. saturated sodium chloride - 250 ml~
ether. The ether extract was washed with 250 ml.
saturated sodium bicarbonate, dried o~er magnesium sulfate ~nd evaporated to give a quantitative yield of the ti~le compound as an oil.
H~MS (m/e) 474.3524 (M. , Calcd. for C33H46O2):
474.3486~, 418, 383, 327, 273 and gl (100~).
Deketalization of trans-3,4-trans-4,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)cycloheptanone ethylene ketal is accomplished in like manner~
8~40~
Cis 3-[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]~
cis-5-methyl-trans-4-(2-methyl-2-propenyl)-cyclohexanol and its axial Isomer Using the procedure of Ex~mple 13, 1.00 g. (2.12 mmole~ of trans-3,4-trans-4,5-3-Z2-benzyloxy-4-(1,1-~im~hylh~p~yl)~hn~1~-~is-5-me~h~l~ ranc-4~ .me~hyl-2-propenyl)cyclohexanon~ gave 248 mg. (25%) of the rans-3,ci~-4,trans-5 isomer of the title compound and 720 g. (71~) of the title compound as oils.
Trans-3, CiS-4, trans-5 Isomer:
~RMS (m/e) 476.3664 (M. , Calcd. for C33~48O2:
47~.3642), ~20, 335, 330, 329 (100~), 312, 311, and 283 Title Compound:
~RMS (m/e) 476.3646 (M+ , Calcd. for C33H~8O2:
476.3642~, 420, 330, 329 and 91 (100%).
Similarly trans-3,4-trans-4,5-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-methyl-trans-4~2-methyl-20 2-propen~l)cycloheptanone is transformed to Ci5-3- ~2-ben~yloxy 4-(1,1-dimethylheptyl)phenyl]-cis-5~methyl--trans-4-(2-methyl-2-propenyl)cycloheptanol and the corres-ponding axial derivative.
~ ~14l~
-154~
EXAMPLE_lO8 Cis-3-~2-Benzyloxy-4-(l,l-dimethylheptyl)phenyl3-trans-4-(3-hydroxy-2-methylpropyl)-cis-5-methylcyclohexanol Using the proc~dure of Example 5, 710 mg. (1.49 mmole) of CiS-3- [2-benzyloxy-4-tl,l-dimethylheptyl)-~hen~ ci~ met~yl-tr~ ;2-metnyl-~-propeny~-cyclohexanol (compound of Example 107~ gave 322 mg.
(44~) o~ diastereomer A and 356 mg. (48%) of dia-stereomer B of title compound as oils.
Dias~ereomer A:
HRMS (m/e) 494~3769 (M. , Calcd. for C33~5003o ~94.3747), 386, 301 and 31 (lO0~).
Diastereomer B~
lS ~RMS (m/e) 494.3790 (M. , Calcdu for C33H50O3:
494~3747) and 9l (lO0~.
In like manner, the remaining alkenyl dexivatives of Example 107 are hydrated to the corresponding alcohol~.
- 155 ~
EXhMPLE 1 O 9 Cis 3-[4 (1,1-dLm~thylheptyl)-2-hydroxyphenyl]-trans 4-(3-h~droxy-2-m~thylprop~ cis-5~methylcyclohexanol Diastereomex A
.
Using the procedure of Example 6, 320 mg. (0.648 ru~.~l~) o~ Ji~a.e~om~~ s~-{~-~e~ l~x~
dimethylheptyl)phenyll-trans-4-(3-hydroxy-2-methyl-~ropyl)-cis 5 methylcyclohexanol (product of Example 108) provided 221 mg. ~84~) of the title compound.
MP 139-141C. (diisopropyl ether-hexane) IR (C~C13) 3588, 3407, 1616 and 157~ cm 1, HRMS tm~e) 404.3247 (M. , Calcd. for C26H44O3:
404.3279), 386, 301, 233, 187, 161 and 147 (100%).
15 Analysis:
Anal. Calcd. fox C26H4~O3: C, 77-17; H~ 10-96-Found : C, 77.41; H, 10.77.
, Diaster omer B
Using the procedure of Example 6, 350 mg. (0.709 mmole) of diastereomer 8 of cis-3-[2-benzyloxy-~ (1,1-dime~h~lheptyl)phenyl]-trarls-4-(3-hydroxy-2-methyl-propyl~-cls~5-methylcyclohexanol (product of Example 108) ga~e 255 mg. (89~) of the title compound.
MP 118-120C. (diisopropyl e~her-hexane).
2S HRMS (m/e) 404.3237 (M~ , Calcd~ for C26H4403:
404.3279), 3~6~ 318, 301 (100~), 233, 187, 167 and 147.
t 18~ )4 EXAMPLE 109 (Conk.
, _ . .
Arlalys is:
Anal. Calcd. for C26H44O3: C, 77.17; H, 10.96~
Found : C, 77.40; ~, 10.76.
By means of this proce~ure, the remaining benzyl ethexs of Example 108 are converted to the corresponding phenols.
8 ~
.- 157 , 7-Oxabicyclo[4.1O0~-1-[2-penzyloxy-4-(1,1-dimethyl-_ heptyl)pheny~-3-heptanone ethylene ketal ~rO a 0C. solution of 5.0 g. (11.2 mmole) of 3~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-3-en-1-one ethylene ketal in 15 mlO of dichloromethane is added 1.26 g. (15 mmole3 of sodium bicarbonate and 2.58 g. (15 mmole) of m-chloroperbenzoic acid. The reaction is stirred overnight at 0C. and then filtered.
~he ~iltrate is diluted with 200 ml~ o~ ether and washed with two 100 ml. portions of saturated sodium bicarbonate.
The organic extract i5 dried over magnesium sulfate and evapo~a ted to yield ~he title compound .
~ :~g~o~
- 15~-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl~-4-hydroxycyclohexanone ethylene ketal Following the procedure of Example 6, 7-oxabi-cyclo[~i.l.O] 1-[2-benzyloxy 4-(1,1-dimethylheptyl)-phenyl3 3-heptanone ethylene ketai is nydrogenatea to give the title compound.
Deketalization acording to the procedure of Example ~ affords the corresponding ketone.
Following the procedures of Example 110, 3-[2-ben~yloxy-4~ dimethylheptyl)phenyl]cyclohept-3-en-1-one is converted to 3-[2-hydroxy-4-(1,1-dimethylheptyl)-phen~l~-4~hydroxycycloheptanone.
~ ~8~'~0~
EX~MPLE 112 Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-hydroxycyclohexanol Sodium ~orohydride r~duction of 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-hydroxycyclohexanone according to the procedure of Example 2 affords the title compound.
Similarly, reduction of 3-[2-hydroxy-4-(1,1-dimethylheptyl~phenyl]~4-hydroxycycloheptanone afords the corresponding alcohol.
~ 18~4d~
PREPARATION A
6-(3-Butenyl)-3-ethoxy-2-cyclohexen-1-one A solution of 25 g. (0.178 mole) of 3-etho~y-2-cyclohexen-l-one in 25 ml. of tetrahydrofuran was added dropwise over a 30 minute period to a -78 C. solution of 0.196 mole of lithium diisopropylamide (from 27.4 ml., 0.196 mole, of diisopropylamine and 85 ml., 0.187 moles of 2.2M n-butyllithium in hexane) in 125 ml. of tetra-hydrofuran. The reaction was then stirred for 30 minutes a~d 65 ml. (0.374 mole) of hexamethylphosphoramide added followed by 38.9 ml. (0.383 mole) of 4-bromo-1-butene.
The reackion was then allowed to warm to room tPmperature, stirred for 1.5 hours and then quenched by addition of 5 mL. (0.277 mole) of water. Most of the solvent was removed on a rotovapor and the residue diluted with 1000 ml.
ice water and 500 ml. ether. The ether phase was separated, washed with two 300 ml. portions o water, dried over magnesium sulfate and evaporated on a rotovapor. Distil- -lation of the resulting crude oil gave 10.1 g. (29%) of ~he ~itle product~
b.p.: 83 C. (0.02 torr) PMR ~CDCl 1.34 (t, J=7Hz, methyl), 1~3 2.6 (m), 3.86 q~ J=7~z, methylene), 4.75-5.2 and 5.45-6.2 (m~
terminal olefin) and 5.26 (s, vinyl H).
In like manner, 6-t3-benzyloxypropyl)-3-ethoxy-2-cyclohexen-l-on was prepared from 12.9 g. (91.9 mmole) of 3-ethoxy~-oyclohexen-1-one and 28.0 g. ~101 mmole) of l-benzyloxy-3-iodopropane. Yield: 17.0 g. (67~).
Puriication was achieved via column chromatography on -161~
500 g. of 5~ ssdium bicarbonate silica gel eluted with 75% ether-hexane.
IR (CHC13) 1632 and 1600 cm 1.
MS (m/e) 288 (M ) PM~ ~CDC1 1.34 (t, J=7Hz, methyl~, 1.4-2.6 (m)~
3.50 (bt, J=6Hz, methylene), 3~85 (q, J=7Hz, methylene), ~.49 ~s~ benzylic methylene), 5~27 (s~ Yinyl Hl and 7.27 (s~ Ph.H)~
P~EPARATION B
.
4-(3 Butenyl)-2-~yclohexen-1-one . .
To a 0 C. slurry of 1.06 g. (26 mmoles) of lithium aluminum hydride in 75 ml. of ether was added a solution S of 10 g~ (51 mmoles) of 6-~3-butenyl)-3~ethoxy-2-cyclo-hexen-l-one in 25 ml, of ether. After stirring for one hour, the reaction was quenched by addition of lOO ml.
of 2~ hydrochloric acid. The quenched mixture was stirred for 30 minutes and then ex-tracted with 300 ml. of ether.
10 The ether extract was washed with 250 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated on a rotovapor. Distillation of the crude oil gave 5.98 g.
(78~) of the title product.
b.p.o 133-136 C. (22 torr) PMR ~cTDSl 1.3~2.7 (m), 4.9-5~4 tm, terminal olefin), 5.5 6.2 (m, terminal olefin), 5.02 (bd, J=~OHz, C-2 vi~yl ~) and 6.91 (bd, J=lOHz, C-3 vinyl H).
Similarly, 4-(3-benzyloxypropyl)-2-cyclohexen-1-one was prepared in 74~ (11.1 g.) yield from 17.0 g. (61.6 ~0 mmole) o~ 6-(3-benzyloxypropyl)-3~ethoxy-2-cyclohexen-1-one.
The product was an oil.
~R (CHC13) 1680 and 1459 cm 1.
PMR ~crDsl 1.2-2.8 ~m), 3.55 (bt, J=6Hz~ methylene), 4.50 ~s, benzylic methylene), 5.92 (dd, J=10 and 2Hz, Yinyl EI), 6.82 (bdt J=lOHz, vinyl H) and 7.33 (s, PhH).
~ .~ 8 ~ 4 PREPARATION C
2-~1,3-Dioxolan-2-yl)ethyltriphenylphosphonium bromide A sol-ltion of 25 g. (0.138 mmole) of 2 (2-bromoethyl~-1,3-dioxolane and 36.2 g. ~0.138 mmole) of triphenyl-phosphine in 30 ml. of toluene was heated at 100 C. for 18 hours. The reaction was cooled to yield two phases.
The toluene phase was decanted and the oil remaining crys-tallize~ at -78~ C. in ethyl acetate. Decantation of ~he ethyl acetate and warming of the crystals to room temperature gave an oil. The oil was dried under vacuum (0.05 torr) at 100 C. for 16 hours to yield lS g. (27%) o the title compound as a solid glass which was ground to a po~cler.
-16~ -PREPARATION D
-8-O~abicyclo[5.1.03octan-2-one To a 0 C. solution of 50.0 g. (0.454 mmole~ of cyclohept 2-en-1-one in 800 ml. o~ methanol was added 85 ml. of 30% hydrogen peroxide (0.75 mole~ followed by the dropwise addition o~ lS ml. of 6N sodium hydroxide (0.09 molel. The reaction was stirred for one hour and then added to il00 ml. ethex-500 ml. petroleum ether.
The ether extract was removed and the aqueous methanol phase extracted wlth ~our 500 ml. portions of petroleum ether and three 300 ml. portions of dichloromethane.
The combined organic extracts were washed with three 800 ml. por~ions of saturated sodium chloride, dried over magnesium ~ulfate and evaporated under reduced lS pressure to an oil (53 g.). The crude oil was purified via vacuum distillation to yield 45.9 g. (80%) of the title compound as an oil. Caution: several ~orceful detonations have occurred during distillation of the crude productO (In general, however, the crude product is pure enough for further synthetic manipulations and distillation can be avoided.) h.p.: 89~90 C. (14 torr~
IR (C~C13) 1695 and 1600 cm 1~ .
MS (m,~e~ 126 (M ), 99, 98, 97 and 84.
~S PMR ~CDCl 0.7-1.5 (m), 1.5-3~0 (m) and 3.48 (d, J=3EIz, C-LH~. 3 ~ :~ 8 ~
_165_ .
PREPARATION E
_Hydroxycycloheptanone To a 25 C. solution of 45.9 g.. (0.364 mole) of 8-oxabicycl.o[5.1~0]octan-2-one in 950 ml. of 10~
a~ueous tetrahydrofuran was added 39.7 g. (1.47 mmoles) of aluminum amalgam~ (The aluminum amalgam was prepared by 15-30 second successive washing of small pieces o~
aluminum foil with 2N sodium hydroxide, distilled water, O.5% mercuric chloride, distilled water, 2N sodium h~droxide, distilled water, 0.5% mercuric chloride, distilled water, ethanol and ether.) The mixture was stirred ~or 2 hours, then filtered through diatomaceous earth. The filtrate was evaporated on a rotovapor, the residue saturated with solid sodium chloride and extracted lS with three 5Q0 ml. portions of ether. The ether e~tract was dried over magnesium sulfate and evaporated to yield 45 g. (97~) o~ the title compound as an oil.
IR (CHC13) 3390, 1695 and 1610 cm 1 MS (mfe) 128 (M ), 110, 100 and 85.
PMR ~cMcl 1.80 (m), 2.42 (m, C-7 methylene)/ 2.89 (d, ~=6Hz, C-2 methylene), 3.40 (bs, OH) and 4.0~ (m, C~3 methine).
~ ~#~0~
_166 _ PREPARATION F
Cycloheptan-1,3-dione To a 10 - 20 C. solution of 20 g. (0.156 mole~
of 3-hydroxycyclohep`~tanone in 700 ml. of acetone was slowly added 5~.9 ml. of 2.67 M Jone's reagent (0.146 mole). The mixture was stirred 15 minutes and then ~uenched ~y addition of 12 ml. of isopropanol. The reaction was ~iltered through diatomaceous earth and the filtrate concentrated on a rotovapor to about 100 ml.
$he residue was diluted with 300 ml. of saturated sodium chloride and then extracted with six 250 ml. portions of ether. The combined organic extract was washed with two 100 ml. portions of saturated sodium bicarbonate, dxied over magnesium sulfate and evaporated under reduced pressure ~aspirator) to yield an oil. Distillation of the crude oil gave 11.5 g. (58~) of the title compound as an oil.
b~p.: 117-~21 C. (14 torr) IR (C~C133 3S09 (weaX~, 1733, 1704 and 1621 cm lu MS (m~e) 126 (M ), 98~ 83 and 70.
PMR ~CDC13 2.0 (m, C-S,~ methylenesj, 2.58 (m, C-4,7 methylene) a~d 3.60 (s, C-2 methylene).
, , ., PREPARATION G
3-Ethoxycyclohept-2-en-1-one _ .
A solution of 220~ g. (0.177 mole) of cycloheptan-1,3-dione and 600 mg. (3.16 mmoles) of p-toluenesulfonic acid monohydrate in 86 ml. o ethanol and 250 ml. of toluene was heated at re~lux for 18 hours. A soxhlet extractor filled with molecl~lar sieves (3A) was used to remove water from the reaction. The reaction was cooled, added to 800 ml. saturated sodium chloride and e~tracted with four 800 ml. portions o~ ether. The combined organic extract was dried over magnesium sulfate and e~aporated to an oil. Distillation of the crude oil gave 25.3 g. (93~) of the title compound as an oil.
b.p.: 74-78 C. (0.10~0.15 torr) IR (Neat) 1645 and 1613 cm 1, MS (m/e) 154 (M ), 135, 109, 98 and 97.
PMR ~cDMcl 1.34 (t, J-7Hæ, methyl), 1.8 (m, C-5,6 methylenes), 2.6 (m, C-4,7 methylene), 3.80 (q, J=7Hz, ether methylene) and 5.37 (s, olefinic H).
PREPARATION H
3-Ethoxy-7-(2-propenyl)cyclohept-~-en-1-one Following Preparation A, 15 g. (97.4 mmole) of 3-ethoxycyclohept-2-en-1-onP and 23.5 g. (0.195 mole) o~ allyl bromide gave 11.4 g. (60%) of the title compound as an oilO
.p.: 80-87 C. (0.05-0.1 torr) IR (Neat) 1650 and 1608 cm 1.
~IS (m/e) 194 (M ) P~ ~CDCl 1.38 (t, J=7Hz, methyl), 1.4-3.1 (m), 3.87 (q, J=7Hz, ether methylene), 4.9-5.3 and 5.4-6.3 (m, olefinic) and 5.42 (s, C-2 vinyl H)~
,~ ~,8~,4~r,~
-1~8~
PRE~ARATION I
4-(2~PropenylJcyclohept-2-en-1-one Following Preparation B, 12.0 g. (61.8 mmole) of 3-e~hoxy~-7 (2-propenyl)cyclohept~2-en-1-one gave 3.0 gO
(33~) of the title compound as an oil.
b.p.: 71-72 C. (0.1 torr) IR ~eat~ 1678 (broad~ cm 1 MS (m/e) 150 (M ) PMR ~CDCl 1.2-3.0 (m), 4.8-6.1 (m, terminal olefin), 5.96 (dd, J=12 and 2Hz, C~2H) and 6.42 (dd, J=12 and 3Hz, C~3~)-PREPARATION J
(R)-l~Bromo-2~benzyloxy-4-tl-methyl-4-phenyl-_ bu~oxy)benzene A mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophe.nol, 20.0 g. (82.6 mmole) of (S)-l-methyl-4-phenylbutyl methane sulfonate and 25.2 g. (200 mmole) of potassijm carbonate in 100 ml. dlmethyl~ormamide was heated at 85 C. for 13.5 hours. The reaction was cooled and ~dded to 500 ml. water-500 ml. ether~ The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil.
The crude oil was pu~ified via column chromatography on 750 g. of silica gel eluted with 10~ ether-hexane to ~5 yield ~3~9 g. (72%) of the title compound as an oil~
~]25 = -11.39 tC = 1.137, CH3Cl) IR (CHC13) 1574 cm 1 E~MS tm/e) 426.1011 (M , calc'd. for C24~2502Br:
426.1012) t 424, 280, 278, 104 and 91.
PMR (CDC13)~ 1.22 (d, J=6Hz, methyl), 1.4-2.0 (m), Z.60 (m, benzylic methylene), 4.24 (m, methine), 5.07 (s, benzyLic methylene), 6.30 (d, J=2Hz and 8Hz, ArH), 6.46 (d, J=2Hz, ArH), 7.17 (s, PhH) and 7.35 (m, PhH).
I~#~33' PREPARATION K
-l-Benzyloxy-3 lodopropane To a solution of 83.3 g. (0.318 mole) triphenyl-phosphine in 200 ml. benzene was added, in four portions, 80 g. (0.318 mole) of iodine. The resultant mixture was stirred 3 hours and th~n 50 ml. (0.618 mole) of pyridine was added followed by the slow addition of 32 g. (0.192 mole) of 3~benzyloxypropanol in 250 ml. of benzene.
The xeaction was stirred 15 hours longer and then diluted with 40 ml~ of methanol. The mixture was filtered through diatomaceous earth and the filtrate evaporated to an oil.
Distillation of the crude oil yielded 28 g. (53~) of the title compound as an oil.
b.p.: 94-97 C. (0.45 torr) PMR (CDC13)~ 2.00 (quintet, J=6Hz, methylene), 3.20 (~, J=6Hz, methylene~, 3.43 (tr J=6Hz, methylene), 4.42 (s, benzylic methylene) and 7.20 (s, PhH).
.
.-- ~
I :~s~n~
-lf o PREPARATION L
_.
(R)-l-Bromo-2-benzyloxy-4-(l~methyl-4-phenylbutoxy)b nzene A mixture o~ 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophenol, 20.0 g. (82.6 mmole) of (S)-l-methyl-4-phenylbutyLme~hane sulfonate and 25.2 g. (200 mmole) of potassium caxbonate in 100 ml. dimethylformamide was heated at 85 C. for 13.5 hours. The re~ction wa~
cooled and ~dded to 500 mlO water-500 ml. ether. The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chroma-tography Oll 750 g. of silica gel eluted with 10~ ether-hexane ~o yield 23.9 g. (72%) of the title compound as lS an oil.
[]25 = ~11.39 (C = 1.137, CH3Cl) IR (CHC13) 1574 cm 1.
HRMS (m~e) 426.1011 (M~, Calc'd for C24H25V2Br, 426.1012), 424, 280~ 278, 104 and 91.
CDC13 1.22 (d, J=6Hz, methyl), 1.4-2.0 (m) 2.60 ~m, benzylic methylene), 4.24 (m, methine), 5.07 ts, benzylic methylene), 6.30 (d~ J=2Hz and 8Hz, ArH), 6.~6 (d, J=2Hz, ArH), 7.17 (S, PhH) and 7.35 (m, PhH)_ 1, ~ 8 ~
--171 _ PREPARATION M
~-(3-Hydroxyphenyl)-2-methylpropanal . _ .
A mixture of 38.9 g. ~0.153 mole) of 2-(3-benzyloxy-phenyl)-2-me-thylpropar.al, 20 g. 5~ Pd/C/50~ water, 1.0 S sodium bicarbonate and 150 ml. ethanol was shaken over-ni~ht under 55 psi of hydrogen. The reaction was filtere~
through diatomaoeous earth, the filt~r cake washed with ethanol and the comblned filtrate evaporated. The residue was reduced as abQve for another 8 hours. Another 10 g.
portion of catalyst was added and the reaction continued overnight. The reaction was worked-up as above and the residue purified via column chromatography on 500 y. of silica gel eluted with 25~ ether-hexane to yield 14 y. ~56~) of the title compound as an oil.
L5 PMR (CDC13~ 42 (s, gem dLmethyl), 6.36 (bs, OH), 6.7-6.9 ~m, ArH), 7.05-7.2 (m, ArH) and 9.62 (s, CHO).
" .
~ ~q ~
PREPARATION ~
2-[3-(Tetrahydropyranyl-2-oxy)phenyl]-2-methylpropanal To a 0C. solution of 11.3 g. (0.0688 mole~ of 2-(3-hydro~yphenyl)-2~me-thylpropanal and 11.1 mlO (0~122 S mole) of dihydropyran in 113 ml. dichloromethane was added several cxyst ls of p-toluenesulfonic acid mono-nydrate. ~Fne reaction was stirred one hour at 0C.
and then added to 60 ml7 saturated sodium bicarbonate -460 ml. ether. The ether extract was washed once with ].00 ml. saturated sodium chlorids, dried over magnesium sulfate and evaporated to yield 15.3 g. (89%) of the title compound as an oil.
IR (CHCl3) 1727, 1603 and 1582 cm 1.
PMR (CDC13) ~ 1.48 (s, gem dimethyl), 1.5-2.1 (m~, 3.4-4.2 (m), 5.37 (m, methine), 6.7-7.4 (m, ArH) and 9.53 (s, C~O).
8~4 PREPARATION o l,l-DLmethyl-l [3-(tetrahydropyranyl-2-oxy)-phenyl]-cis-2-heptene To a 15C. solution of 75.5 mmole of dimsyl sodium (from sodium hydride and dimethyl sulfoxide) in 3a ~1~ dime~hyl sulo~ide was added portionwise7 31.2 g. (75.5 mmole) of n-pentyltriphenylphosphonium bromide~ The resultant slurry was stirred 30 minu~es and ~he 15.3 g. (61.6 mmole) of 2-[3-(tetrahydro-pyranyL-2-oxy)phenyl]-2-methylpropanal was added over lS minutes. The reaction mixture was stirred 50 minutes at 15C. and then added to 800 ml. ice -800 ml. ether. The a~ueous phase was extracted twice with 400 ml~ of ether. The combined ether extract was lS wa~hed once with 250 ml.,water and once with 250 mlO
saturated sodium chloride, dried over maynesium sul-fate and evaporated to yield an oil. Triphenylphos-phine oxide was removed by crystallization from pentane. The remaining oily residue was puri~ied via column chromatography on 1 kg. of silica gel eluted with 0.75~ ether-h~xane o yield 17.7 g. (95%) o~ the title compound as an oil.
IR (CMC13) 1603 and 1581 cm 1, P~R ~CDC13) ~ 0.76 (ml terminal CH3), 1.20 (st gem 2S dimethyl), 3.3-4.1 (m), 4,9_S~a (m, 2H), 5.56 (d, J=12~z) and 6.6-7.3 (m, ArH).
~ ~ ~s ~
--17~1--P REPARAT I ON P
Trans~3 methyl-4-(2-propenyl)cyclohexanone ... .. ..~
To a 0C. solution of 0.282 mole of dimethyl copper lithium in 200 ml. of tetrahydrofuran was S slowly added a solution of 25.6 g. (0.188 mole) of 4-~2 propenyl)cyciohex-2-en-~one in ~0 ml. ~f tetr~
hydrofuran. The reaction was stirred 15 minutes and then quenched by addition to a 0C. saturated solution (500 ml.) of ammonium chloride. The quenched reaction was extracted with 500 ml. ether. The ether extract was w~shed with 500 ml. saturated ammonium chloride, dried over magn sium sulfate and evaporated to an oil which was purified via distillation to yield 15.5 g.
(5$%) of the title compound.
BP 110-113C. (15 torx) ~R (CH~13) 1710 and 1640 cm 1.
MS (m/e~ 152 (M ), 136, 110.
~nalysis:
Calcd. for CloH16O: C, 78.8g; H, 10.59.
Found : C, 78.76; H, 10.24.
P~R (CDC13) ~ 1.05 (d, J=6Hz, methyl), 1.0-3.0 (m), 4,8-5.3 (m, vinyl H) and 5.4-6.1 (m, vinyl H).
SLmiliarly, trans~3-methyl-4-(2-propenyl)cyclo-~heptanone is produced from 4-(2-propenyl)cyclohept-2-25 e~ one.
~ ~8~4(~4 -175_ PREPARATION Q
~-Methyl-4 (2-propenyl)-2-phenylsulenyl-cyclohexanone To a 0C. mixture of 16.9 g. (0.109 mole) of methyl benzenesulfinate and 8~68 g. (0.217 mole~ of potassium hydride in 100 ml. of dimethoxyethane was - slowly added a solution of 15.0 g. (0.0987 mole) of trans-3-methyl-4-(2-propenyl)cyclohexanone in 50 ml.
of dimethoxyethane~ The reaction was stirred 30 minutes longer at 0C. and then cautiously added to 500 ml. of ice-saturated sodium chloride and 45 ml. 6N
hydrochloric acid. The quenched reaction micture was extracted once with 300 ml. ether and once with 200 ml. dichloromethane. The organic extract was lS driecl over magnesium sulfate and evaporated to give a quantitative yield o~ the title compound as a semisolid mixture of axial and equatorial sulfenates. Crystal-lization from ether yields 7.8 g. of pure axial sul-~ena~e.
A:cial Sulfenate:
PMR (CDCl3) ~ 1.05 (d, J=5Hz, methyl~, 1.0-1`
2.7 (m), 3.39 (dd, J=ll and 6Hz, CHS), 4.7-5.2 (m, vinyl H), 5.3~6.1 tm, vinyl H) and 7.4 (m, PhH).
~5 In like manner, 3-methyl-4-(2-propenyl)cyclohept-2-en-1-one is converted to 5-methyl-4~ propenyl)-2-phenylsulfenylcycloheptanone.
- \
PREPARATION R
Trans-5-methyl-4-(2-propenyl)cyclohex-2-en-l-one ~ mi~ture of 96.7 mmole of 5-methyl-4-(2-propenyl)-2-phenylsulfenylcyclohexanone and lO g, (lOO mmole) of S calcium carbonate in 300 ml. of toluene was heated at C for ~0 mi n~es. The re~ction ~ c~o~
magnesium sulfate added and filtered. The filtrate was evaporated and the residue purified via column chromatography on 300 g. of silica gel eluted with 20%
ether-hexane and then distillation to yield 7.61 g.
~52~) of the title compound.
BP 50~C. (0.03 torr).
PMR (CDCl3) ~ l.ll (d, J=6Hz, CH3), 1.3-2.g (m) 4.8-5.3 (m, vinyl H~, 5.3-6.2 (m, vinyl H), 5.95 (bd, J=lOH~, C-2 H) and 6.80 (bd, J=lOH2, C-3 H).
By means of this procedure, 5-methyl-4-(2-propenyl)-2-phenylsulfenylcycloheptanone is converted to trans S-methyl-4-(2-propenyl)cyclohept-2-en-l-one.
PR~ARATION S
3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cyclohex-3-en-l~one ethylene ketal A solution of 500 mg. of 3-t2~benzYloxy-4-(1~1-dime~hylheptyl)phenyl]cyclohex~2-en-1-one, 7.8 g. o~
ethylene glycol, 375 mg. of hydroquinone and 50 mg. of ~-toluenesulfonic acid monohydrate in 50 ml. of benzene i5 hea-ted at reflux for 12 hours using a Dean Star.~ condensor filled with 3~ molecular sieves. The reaction is cooled, added to 500 ml. saturated sodium bicarbonate and the quenched mixture extracted wi-th three 150 ml. portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid is puri~ied via column chromatography on 50 g. of silica lS gel eluted with 50% ether-petroleum ether to yield the title product.
Similar1y, 3-[2-benzyloxy-4-tl,l-dimethylheptyl)-phenyl]cyclohept-3-ex~ one ethylene ketal is prepared Prom 3-~2-benzyloxy~4-(1,1-dimethylheptyl)phenyl~-cyclohept-2-en-1-one.
PREPARATION T
-3-[2-~enzyloxy-4-(l,l-dimethylheptyl)phenyl]-cYclohex-2~enone A solution of 3.89 g. (l0 mmoles) of 2-(3-benzyl-oxy 4-bromophenyl)-2-methyloctane in l0 ml. of tetra-hydro~uran was slowly added to 360 m~. 114.4 mmoles~
o~ 70-80 m~sh magnesium metal. The resulting mixtuxe was refluxed for 30 minutes and then cooled to 0C.
To this solution was slowly added a solution of l.~0 g.
L~ (l0 mmoles) of 3-ethoxy-2-cyclohexen-l-one in 3 ml. of tetrahydrouran. The reaction mixture was stirred for 30 minutes at 0C. and then quenched by the addition o~ 20 ml. of lN sulfuric acid and heating on the steam bath ~or 30 minutes. It was then cooled and added to L5 200 ml, of ether - 200 ml. of water. The organic extrac~ was washed successively with 200 ml. of satu-rated sodium b1carbonate and 200 ml. o~ saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified via column chrom~tography on 170 g. of silica gel eluted with l:l ether:pentane to yield 2.5 g. (54~) of the title compound as an oil.
IR (CHCl3) 1667, 1610 and l558 cm l.
MS (m/e) 404 (M ), 3l9, 313 and 9l.
In like manner, 3-~2-benzyloxy-4-(l,l-dimethyl-heptyl)phenyl]cyclohepten-2-enone is prepared ~rom 3-ethoxy-2 cyclohepten-l-one.
~ ~8~L~()4 _179 _ PREPARATION U
6-[2-Benzyloxy 4-(l,l-dimethylheptyl~phenyl]-cYclohept-3 en-l-one To a 0C. slurry of 2.L9 g~ ~0.055 mole) of potassium hydride in 20 ml. of dimethoxyethane is ad~e~ 4.3~ 0.0~ -mule~ o~ ~ei*yi pnenylsulrinate.
To the resultant mixture is added, dropwise over a 30 minute period, a solution of 9~82 g. ~0.024 mole) of 3-~2-benzyloxy-~-(1,1-dimethylheptyl)phenyl]cyclo-heptanone in 20 ml. of dimethoxyethane. The reactionis stirred one hour at 0C. and then quenched by dropwise addition of l ml. of water. The quenched reaction mixture is added to 15 ml. ether ~- 15 ml.
dichloromethane -- 12.5 ml. 6N HCl-40 ml. satura~ed sodium chloride. The aqueous phase is extracted with another lS ml. portion of dichloromethane. The com-bined organic extract is dried over magnesium sulfate and evaporated to a semisolid. It is used as is in the next step.
The crude product thus obtained is mixed with 2.68 ~. (0.026~ mole) of calcium carbonate in lO0 ml.
of toluene and heated at 110C. for 30 minutesO The reaction mixture is cooled, filtered through magnesium sulfate and the filtrate evaporated on a rotovapor to yield an oil which was purified via column chroma-tography on 500 g. of silica gel eluted with 39%
ether-hexane to yield the title compound.
oE silica gel eluted in 10 ml. fractions with ether to lS yield 711 mq. (72%) of the ti~le compound as an oil.
PMR (CDC13) ~ 0.88 (m, terminal ~ethyl), 1.28 (d, ~ æ, me~hyl), 2.95 (m), 3.40 (s, methoxy), 3.70 (m~
methylene), 4.22 (m~ methine), 6.35 (m, ArH) and 6.82 (d, J=8H2, Ar~).
EIRMS (m/e) 390. 2769 (M , calc'd. for C24H38O4:
390.2760), 304, 289, 273, 192, 191, 177 and 161.
ln~20 C~ = +3.17 (c = 1~29 methanol) d-Trans-3-[2-hydroxy-4-(2-octyloxy)phenyl~-4--_ _ (3-h~droxypropyl)c~clohexanane ~ mixture o~ 711 mg. (1.82 mmole) of d-3,4-d.ihydro-2-me thoxy-7- ~ ( 2-octyl)oxy]-2,4-propano-2H-l-benzo~
pyran~9-propanol, 25 ml. tetrahydrofuran and 15 ml. lN
hyd~ochl~ric acid was heated 1.5 hours at reflux. The reaction was cooled and diluted with 200 ml. sa~urated sodium chloride-200 ml. ether. The ether e~trac~ was washed with 200 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to give a quanti~
tative yield or the title compound as an oil.
HRMS (m~e) 376.2592 (M , calc'd. for C23H360~:
376.~604), 290, 275, 264, 179, 178, 177, 164, 163 and 161.
_130-~X~MPL~ a s d-Cis-3-~2-hyd~oxy-4-(2-octyloxy)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol and the trans-3, CiS-4 isomer _ _ _ Using the procedure of Example 2, 684 mg. (1.82 mmole) of d-trans-3 ~2-hydroxy-4-(2-octyloxy)phenyl]-4-(3-hydroxypropyl)c~clohexanone yielded in order of elution with 50~ ether-dichloromethane, 420 mg. t61~) of the title compound and 75 mg~ j of the trans-3, C15-4 isomer as oils.
10 . Cis~3, trans-~
[a]20 C- = ~4.26 (c = 1.01, methanol) EIRMS (m/e) 378.2762 (M , calc'd~ for C23~3~0~:
373.2760), 266, 2~18, 147 and 123.
Trans~3, cis-~L
H~MS (m/e) 378.2789 (M , calcld. for C23H38O4:
378.2760), ~66, 248 and 123.
The compounds tabulated below are prepared according to the procedures of Examples 83 and 84 ~rom the appro~
priate reactant CH3 SO2-O-Z-W.
~H
(~1~o (alk2)-W
CH~OH
2 ) w (CH~)4 C6~5 CH(CH3~c~2)3 C6H5 CH(CH3)(c~2)5 C6H5 ~ 131 ~
(alk2 ) W
C~I5CH3) (CX2) 3 4--ClC6~4 C~l~C~3) (C~2) 3 4-FC~jH4 CH (CEI3 ) (CH2 ~ 5 H
(CH2~ 11 El CH(C~3) (CH2) 3 4-pyridyl ( C~I2 ) 4 2-pyridyl (CH2) 72-pyridyl 2) 13 H
(CH2) 3 C 6 5 I ~$~
-132_ 1-3~4-Dihydro-2~methoxy-7-L(2-octyl)oxy3 2,4-propano-2H--l-benzopyran-9-propanol Using the procedure of Example 83, 700 mg~ (2.52 mmole) of 3,4~dihydro-2~methoxy-7-hydroxy-2,4-propano-2H-l-~enzopyran-9~propanol and 786 mg. (3.78 mmole) of d-2-octylmethanesulfonate gave 742 mg. (75%) of the title compo~md as an oil.
PMR (CDC13) ~ 0u88 (m, methyl), 1.29 (d, J-6Hz, methyl), 2.g2 (m, methine), 3,38 (s, methoxy), 3.7 (m, methylene), 4.25 (m, methine), 6.3 (m, Ar~) and 6.80 ~d, ~=8EIz, ArH).
~a320 = 1.76 (c = 1.33, methanol) H~MS (m/e) 390.2763 (M , calc'd. for C24H38O4 390.2769), 304, 289, 278, 273, 246, 192, 191, 177 and EX~MPLE 87 l-Trans 3-[2-hydroxy-4-(2-octyloxy)phenyl]-4-= (3-hydroxypropyl)cyclohexanone Using the procedure o~ Example 84, 742 mg. ~1,90 m~lole) o 1-3,4-dihydro-2-methoxy-7-[(2-octyl)oxy~-2,-l-propano-2H-l-~enzopyran-9-propanol ga~e a quantitative yiel~ of title compou~d as an oil.
HRMS (mfe) 376.2624 (M+, calc'd. for C23~I360~:
376.2592), 264, 179, 178 and 177.
4 ~I L~
~133-l-Cis-3- r 2-hydroxy-4-(2-octyloxy)phenyl]-trans-4-(3-hydroxyprop~l)cyclohexanol and the trans-3,cis-4 isomer Using the procedure of Example 5, 714 mg. (1.90 S mmole) of l-trans-3~~2 hydroxy-4-(2-octyloxy)phenyl~-4-(3-hydro~Yypropyl)cyclohexanone afforded 483 mg. (67%) of the title compound and lDl mg~ ~14~ of ~hg tr ns-~5 CiS-'i isomer as oils.
Cis~3, trans-4 ~ O C = -5,214 (c = 1.13, methanol) HRMS (m/e) 378~2775 (M~, calc'd~ for C23H3~O4:
378.2760), 26G, 249, 248, 147 and 123.
?ranS-3, CiS-4 _ __ HRMS (m/e) 378.2767 (M+, calc'd. for C23H38O4.
378.2760), 266, 248, 189, 149, 147 and 123.
Followlng the ~rocedures of Examples 77 - 81, 4-(2-propenyl~-2-cycloheptenone is converted to trans-3~(2,4-dihydroxyphenyl)-4-(3-hydroxypxopyl)cyclo-heptanone.
- ~ \
~ ~ 1 4 ~ L~
-.134-Repetition o~ the procedures of Examples 82 - 88, but using trans-3-~2,4-dihydroxyphenyl)-4-(3-hydroxy-propyl)cyclvheptanone as reactant in Example 82 proc~dure, and the appropriate CH3S02-0-Z-W alkylating agent affords the following compounds:
~H
(~ fH
~0- (alk2)-W
(alX2 ) W
C~l (CH3 ) ~CH;l! ) 6 H
CH(C~3)(CH2)5 H
(CH2)11 N
C~(CH3)(CH~)3 C6HS
(C~2)4 C6HS
C~(CH3)(C~2)3 4-FC6H4 (CH2)4 4-pyridyl !135-Trans-4-[2-Propenyl)-3-[2-(tetrahydropyranyl-2-oxy~-4~(1,1-dimethyL)-cis-2-he~tenyl)phenyl]cyclohexanone _ . . . ~ ~
To a 0C. solution of 2.0 g. (6.62 mmole) of 1,1-dimethyl-1-[3-(tetrahydrop~ranyl-2-oxy)phenyl3 -cis-2-hepta~e and 84~ mg. t7~28 mmole) of tetramethylethylene diamine in 10 ml~ of ether was slowly added 3.17 ml.
(7.28 mmole~ of n-butyllithium (in hexane). The resultant solution was stirxed 5 minutes at 0C. and then refluxed for 70 minutes. The xesultant was then cooled to -78C.
To a ~C. solution of 597 mg. (7.28 mmole) of 1-he.Yyne in 10 mlO of tetrahydr~furan is slowly added 3.L7 ml. (7.28 mmole) of m-butyllithium (in hexane).
The resultant solution was stirred 10 minutes at 0C.
and then slowly added to a 0C. slurry of 1.38 g.
(7.28 mmole~ of cuprous iodide in 10 ml. of tetra-hydrofuran. The resultant yellow slurry was stixred 30 minutes at 0C. and then slowly added to the above prepared -7~C~ solution of ar~l lithium reagent. The resultant ye~low mixture was stirred 10 minutes at -7~'C. and then 900 mg. (6.62 ~mole) of 4-(2-propenyL)-cyclohe:c-2-en-1-one is added dropwise~ Stirring was continued for 10 minutes and then the reaction was placed in a -~O~'C. cooling bath and allowed ~o warm to -2q~. over 20 minutes. The reaction was quenched by addition to 200 ml. of cold saturated ammonium chloride ~rought to pH 10 with saturated ammonium hy-droxide. The quenched reaction mi~ture was ext~~acted with 300 ml. of ether. The ether extrac~ was dried ~ver magnesium sulfate and eva~orated to an oil which was purlfied via column chrcmatogra~hy on 200 g. of silica gel eluted in 15 ml. 'ractions wit~ 0~ ethe-~hexane to ~ield ~-om _rac. cns ~0-63, 2.36 g. (82~) of the ti~le ccmpo~nd as an oil.
-,:
n ~
E,YAMPLE 91 (Cont.) I~ (C~C13) 1709, 1641, 1610 and 1571 cm 1, HRMS (m/e) 354.2569 (P. -C5H80: Calcd. for C24H32O2:
354~2550), 272, 271, 161, 137 and 85 (100~.
P~R tCDCl~) ~ 0.69 (m, terminal CH3), 1.41 (s, gem dimethyl), 0.8-4.2 (series of m), 4.7-5.6 (m, olefinic H and THP methine), 5.62 (d, J=12Hz, vinyl H) and 6.7-7.3 (m, ArH).
Trans-4-(2-Propenyl)-cis-3-[2-(tetrahydropyranyl-2-o~y)~ dimethyl-cis 2-hQptenyl)phenyl]-cyclohexanol and the cls-4,trans-3 isomer ~'o a -78C~ ~olution of 20~0 g. (45.7 mmole) of trans-4-(2-propenyl)-3-f2-(te$rahydr~pyr2nyl-~-oxy)~~-__ ~l,l-dimethyl-cis-2-heptenyl)phenyl]cyclohexanol in 200 ml. of me~hanol was added in one portion 5.20 g.
(137 l~mole~ Oe sodium borohydride. The reaction was stirxed overnight at ~78C. and then allowed to warm to ODC. The reaction was quenched with 10 ml. satu-rated sodium chloride and then concentrated on a rotova~or. The residue was diluted with S00 ml.
saturated sodium chLoride and 500 ml. ether. The et.her extract was washed once with 250 ml. saturated s~dium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 1 kg. of silica gel eluted with 3a~ ether~hexane to yield in order of elution 2.20 g~ ) of the cis-4, trans-3 isomer, 0.74 g.
(4%) of mixture ~nd 17.0 g. (S5%) of the title compound as oils.
~itle Compound:
IR (CHC13) 3593, 3464, 1640, 1610 and 1571 cm 1.
HRMS (m/e) 3S6.2709 (P. -C5H8O, Calcd. for C2~H36O2:
356.2706), 297, 273, 255, 124 and 8S (100%).
P~IR (CDC13) ~ 0.70 (m, terminal CH3), 1.42 (s, gem dimethyl), 2.8 (bm, benzylic methine), 3.4 4.1 (m, carbinol methine and OCH2), 4.6-5.5 (m, vinyl H and THP me~hine), 5.60 (d, J=L
Hz, ~iny; H) and 6.8-7.2 (m, ArH).
-138 ~
XAMPLE ~3 Trans-4-t3~ droxypropyl)-c 3-[2-(tetrahydro-pyranyl-2-oxy)-~(1,1-dimethy.l cls-2-heptenyl~
phenyl]cyclohexa~ol To a -54C. solution of 13.3 g. (0.0302 mole) of rans-4-(2 pxop~nyl)-ClS-3-[ 2-(tetrahydropyranyl-2-oxy)-4-(1,1-di~lethyl-cis-2-~eptenyl)p~ny~3cyclDne~anoi in 100 ml. of tetxahydrofuran was slowly added 35.1 ml.
(0.0351 mole) o boran-tetrahydrofuran (lM in tetxa-hydrofuran), wi~h stirring. After 30 minutes another 50 ml. of tetrahydrofuran was added and ~he reac~ion stirred 30 minutes longer, then quenched by addition of 40 ml. ~0.12 mole) of 3N sodium hydroxide and oxidized hy addition of 10 ml. (0.112 mole) o~ 30% hydrogen peroxide. After stirring 20 minukPs the reaction was added to 50Q ml. saturated sodium chloride - ~00 ml.
ether. The aqueous phase was extxacted with another 2 5 0 ~1 . portion of ether and the combined ether extract dried over magnesium sulfate and evapoxated to an oil. Th~ cru~e oil was puri~ied via column chroma-tography on 1 ~g. of silica gel eluted with 80% ether-hexane to 3~ methanol-ether to yield in ~rder of elution .
600 mg. (5%) of unreacted starting material, 7O45 g.
(54%~ of the title compound as a~ oil, 1.3~ g. (12%) of trans-4-(3 ~ydro~cypropyl) -ClS-3 - ~2-hydroxy-4-(1,1-di-methyl-cis-~-heptenyl~phenyl]cyclohexanol (phenolic product) and 1.7B g. tl3%) of trans-4-(3-hydroxy propyl)-cis-3-[2-ttetxahydropyranyl-2-oxy)-4-(1,1-dimethyl-3-hydroxyheptyl)phenyl]cyclohexanol ( Triol -THP).
~ .~ 8 ~
--139 _ Example 93 (Cont ) Ti tle Compound:
HRMS (m/e~ 874.2a31 (P. -C5H80, Calcd. for C24H3803:
37'1.2811), 356~ 242, 151 and 85.
PMR(CDC13) C 0.72 (m, terminal CH3), 1.40 (s, gem dimethyl) ~ 2.,8 (m, benzylic methine), 3.47 (m, CH2OH), 3 ~ 2-4 . 2 (m, car~inol methine and -CEI20-), 4 . 9-S . 5 (vinyl H and THP methine), 5 . 62 (d, J=llHz, vinyl H) and 6 . 9-7 . 2 (m, ArH).
10 Pheno tic Pxoduct:
~lS (m/e) 374.2839 (M+, Cal::d. for C24H3803:
37~.2811) r 356, 341, 299~ 273 and ~70.
Triol-T~IP:
HRMS (m/e) 392 . 2949 (P. -C5~80, Calcd. for C24H4004:
392.2916), 374, 292, 274, 165 a~d 85 (100~).
4 ~ ~
1~0 .
~XAMPLE 9~
Trans-4-(3-d-Mandeloyloxy)-c1s-3-[2-hydroxy-4-(l,l~dLmethyl~cis-2-heptenyl)phenyl]-1-d-mandeloyloxy-cYclohexane A mixture of 6.00 g. (13.1 mmole) of trans-4-(3-hydrQXyprOpyl) -CiS-3- [2-(tetrahydropyranyl-2-oxy)-4-(l,l-dimethyl-cis-2-heptenyl)phenyl]cycloh xanol, 9.96 g. (6S.5 mmole) d-mandelic acid and 498 mg.
2.62 mmole) p-toluenesulfonic acid monohydrate in 250 ml~
of benzene was heated at reflux. Water was removed via a 3A molecular sieve filled soxhlet extractor. The xeaction was heated at reflux for 160 minutes wi~h additional portions of p-toluenesulfonic acid mono hydrate added at 40, 80 and 120 minutes. The reaction was cooled and added to 500 ml. saturated sodium bi-carbona~e - 500 ml~ ~ther. The aqueous phase was ex O
tracted with a second 250 ml. portion of ether and the combined ether extract dried over magnesium sulfate and av~porated to an oil. The crud~ product w~s purified vi~ column chromatography on 800 g. of silica gel eluted wit~ 55% e~her-hexane to yield order o~ elution 2.25 g.
(2~) o~ diastereomer A of the title compound, 20 0 g.
(24~) of a mixtu~e and 4.0 g. (48~) of slightly impur~
diastereomer B o the title compound as ~ils.
Dias~reomer A:
20~ ]CEt3o~ = + 31.62 (C=1.85) P~R ~CDC13) ~ 0.68 (m, terminal CH3), 1.37 (s, gem dimathyl), 3.4 (bd, J-6Hz, OH), 3.93 (bt, J=
6Hz, -CH2O-), 4.75 (m, OH), 5.02 (m, C OH), 5.0-5.7 (m~ vinyl H), 6.6-6.9 (m, ArH~, 7.23 and 7.26 (s, PhH).
., 4~)~
-141_ EX~MPLE 95 Trans-4-(3-hydroxypropyl)-cis-3-[2-hydroxy-4-(l,l-dimethyl-cis-2-heptenyl)phenyl]cycloh xanol . _ . . . . _ A mixture of 3.10 g. (4.82 ~mole) of diastereomex 5 A of trans~4- (3-d-mandeloyloxy) -cis-3 - [2-hydxoxy-4-(l,l-dimethyl-cis-2-heptenyl)phenyl]-1-d-mandeloyloxy-cyclohexane, 5,3~ g. ~38.6 mmoLe3 potassi~n carbona~e~
40 ml. methan~l, 40 mlO tetrahydrofuran and 10 ml. water was s~irred at Z5~C. for 24 hours. The reaction was evapoxated on a rotovapor and the residue dissolv~d in 250 ml. ether - 250 ml~ saturated sodium chloride. The aqueous phase was ex-tracted with two additional 150 ml.
portions o~ ether, the combined ether extract dried over magnesium. sulfate and evaporated to an oil . The crude lS produc~ was purified via column chromatography on 150 g.
of silica gel eluted with ether to yield 1.3 g. (72%) of the title compound.
~P: 95-97C. (Diisopropyl ether-haxane) ~oo[~]CH30H = -56 32 ffRMS (m~e) 374.2319 (M~ , Calcd. for C24~3803:
37~.2811), 356, 213, 187; 16~ 7, 124, 121, and 93~
P~R (250 mH2, CDC13) ~ 0.73 ~m, te~ninal methyl), 1.39 (s, gem dimethyl), 2.03 tm, CH2 vinylic), 2.72 (m, benzylic methine), 3.47 (m, CH~OH), 3~7~ (m, CHOH), 5.07 (bs, OH), 5.22 and 5.27 (dt, J=11.51 and 7.31 Hz, vinyl H), 5.61 (dt, J=ll.Sl and 1.6 Hz, vinyl H3, 6.73 (d, J=1.64 Hz, ArH), 6.91 (dd, J=8.22 and 1.8~ Hz, ArH) and 7.02 (d, J=8.04 Hz, ArH).
~XAMPLE 96 T.ans 4-(3~hydroxypropyl)-cis-3-[2-hydroxy-4-(l,l-dimethylheptyl)phenyl]c clohexanol ~ mixture of 50.0 mg. (0.134 mmole) of (-)-trans-5 4-(3~hydroxypropyl)-cis-3-[2-hydroxy-4-(1,1-dimethyl-ci ~-heptenyl)phenyl]cyclohexanol and 50 mg. of 10~
palladium on ca.rbon in 5 ml. of dry tetrahydrDf~7r_n was stirred under one abmosphere of hydrogen for 30 minutes.
The reaction was filtered through diatomaceous earth L0 with te~rahydrofuran and the filtrate evaporated to ~ield 47.9 mg. (95%) of the title compouIld as an oil.
20[~]DH3H = -36 12 .
~ 3_ Trans-3,4,trans-4,5-3-[2-benzyloxy-4~ dlmethyl-heptyl)phenyl]-5-methyl-4-(2-propenyl ? cyclohexanone . _ Using the procedure of Example l, 7.5 g. (50 mmole) S Of trans-5-methyl-~-(2-propenyl)cyclohex-2-en-l-one and 2~1.3 g. (62.5 mmole) of l-benzyloxy-2-bromo-5-(l,l-di-meth~lheptyl~benzene gave 13.0 g. ~57~ of the title compound as an oil.
IR (CHCl3) 1709, 1639, 1609 and 1568 cm l, HRMS (m/e) 460.3353 ~M+ , Calcd. for C32H44O2:
460.3330), 375, 370, 369 and 9l (lO0~).
PMR (CDCl3) ~ 0.82 (m, terminal CH3), 1.26 (s, gem, dimethyl), 4.5-5.1 (m, vinyl H), 5.00 (s, benzylmethylane), 5.3-5.8 (vinyl H), 6.6~7.l (m, ArH) and 7.25 (bs, PhH).
In like manner, trans-3~4-trans-4,5-3-[2-benzyloxy-4~ ( 1, 1 -dimethylheptyl ) phenyl]-5-methyl-4 (2-propenyl)-cycloheptanone is prepared from trans-5-methyl-4-(2-prop~nyl)cyclohept-2-en-l-~ne.
~ ~8~
-1~4 -Cis-3-L2-benzyloxy-4-(1,1-dimethylheptyl)phenyl] CiS-5-methyl-trans-4-(2-propenyl)cyclohexanol _ _ _ . . . _ . .
Using the procedure of Example 2, 6.0 gO (13.0 mmole3 of trans-3,4-trans, 4,5-3-[2-benzyloxy~4-(1,1-dimethylhep-tyl)phenyl]-S-methyl-4-(2--propenyl)cyclohex-anone gave 1.1 g. (18~ o~ the cls-~,trans-3,trans-~
isomer of the ~itle compound, 1.077 g. (17%) of a mi~-ture and 2.79 (46%) of the title compound as an oil.
Cis-~,Trans-3,Trans-5 Isomer-HRMS (m/e) 462.3501 (M. F Calcd. for C32H4602:
362.3486)~ 377, 269, 227 and 91 (100~).
PMR (CDC13) ~ 0.82 (m, terminal methyl), 0.95 (d~
J=6Hz, methyl), 1.23 (s, gem dimethyl), 3.5 lS (m, benzylic methine) r 4.13 (m, carbirlol . methine~, 4.6-5.0 (m~ vinyl H), 5.05 (s, benzylic methylene), 5.2 6.1 (m, vinyl H), 6.35 (mr ArH~, 7.05 (d~ J=8Hz, ArH~ and 7.3 (bs, PhH).
20 Title Compound: .
IR (CHC13) 3596, 3463, 1~39, 1609 and 1570 cm 1.
H~MS (m/e) 462.3499 (M. , Calcd. for C32H460~:
'~62.3501), 377, 353, 269, 227 and 91 (100~).
P~R (CDC13) ~ 0.83, (m, terminal C~3), 1.25 (s, gem dimethyl~, 3.2 (m, benzylic methine), 3.62 (bm, arbinol methine), 405-5.0 (m, vinyl H), 5.02 (s, benæyl~c methylene), 5.3-6.1 (m, vinyl H), 6.82 (m, ArH), 7.00 (d, J=
3HZr Ar~) and 7.35 (bs, Ph~).
~ollowing the above procedure trans-3,4-trans-4,5-3~[2~benz~10xy-4-(l,l-dimethylhep~yl)phenyl~-5-methyl-trans-4-(2-propenyl)cycloheptanone is prepared from the correspondingly substituted cyclohept-2-en-1-one.
4 ~
Trans-3,4-Trans,4,5-3-~2-benzyloxy-4-(1,1-dimethyl-hep~yl)phenyl]-5-methyl-4-(2-propenyl)cyclo-hexanone ethylene ketal A mixture of 7~0 g~ (15.2 mmole) of trans-3,4-trans,~l,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~
~-methyl-4-~2 propenyl~cyclohexanone/ 8.47 ml. ~152 mmole) of e-thylene glycol and 289 mg~ (1.52 ~mole) of ~-~oluenesulfonic acid monohydrate was heated at reflux for 2.5 hours~ Water was removed via a soxhlet extractor Eilled with 3A sieves. The reaction was cooled and added to 250 ml. saturated sodium bicarbonate - 250 ml. ether.
The ether extract was dried over magnesium sulfate and evapora~ed to an oil. The crude product was purified via column chromatography on 300 g. of silica gel eluted with 20~ ether-hexane to yield 5.2 g. (68~) o~ the title compound a~ an oil.
IR (CHC13) 163~, 1608 and 1569 cm 1 ÇIRMS ~m/e) 504.3579 t~. , Calcd. for C34H480 50~.3591), 419, 413, 407 and 91 (100~).
PMR ~CDC13) ~ 0.82 (m, terminal methyl), 0.99 (d, J=6-~z, OEI3), 1.25 (s, gem dimethyl), 3.4 (m, benzylic methine), 3.90 (s, ethylene lcetal), 4.4-5.0 (m, ~inyl H), 5.03 (s, benzylic ~S methylene), 503-6.2 (m, vinyl H), 6.80 (m~
ArH), 7.00 (d, J-8Hz, ArH) and 7.35 (bs, PhH).
The ethyLene ketal o~ trans-3,4-trans-4,5-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl~4~(2-propen~l)cycloheptanone is prepared in liXe manner from the corresponding cycloheptanone~
_146-Cis-3-[4-(1,1-dimethylheptyl)~2-hydroxyphenyl]-.. . cis-5-methylcyclohexanol To a 0C. solution of 900 mg. (1.95 mmole) of CiS-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~ -5iS-5-methyl-trans-~-(2-propenyl)cyclohe~ancl in 2 ml~ of ether was added ~.1 ml. ~11.7 mmole) of n-butyllithium (in hexane). The reaction was stirred 10 hours at 25C. and then added to 200 ml. ether 200 ml. saturated ammonium chLoride. The ether extract was dried over magnesium sul.fate and evaporated to an oil. This oil was cxystal-lized in hexane to yield 495 mg. (68~ of the ~itl~
compound.
MP 149-150 QC. . (hexane) ~R (CHC13) 3455, 3253, 1643, 1617 and 1583 cm 1.
HRMS (m/e) 372.3050 (M. , Calcd. for C25HA 02:
. 372.3018), 312, 288, 287 (100%), 272, 269, 227, 187, 161, 147 and 135.
A ~ :
Analysis Calcd. For C25H~0O2~ C, 80.59; Hl 10.8~
Found ~ C, 80.35; H, 10.81 De~enzylation o~ cis-3-[2-benzyloxy-4-(1,1-dimethyl-heptyl.) phenyl]-cls-5-methyl-_rans-4-(2-propenyl)cyclo-heptanol is carried out in llke manner.
~814~
-1~7-Cis-3-C2-Benzyloxy 4-(1,1-dimethylheptyl)phenyl~-trans-4-(3-hydroxypropyl) -CiS 5-methylcyclohexanol _ . ~
Using the procedure of Example 5, 900 mg. (1.95 mmole) of cls-3-~2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl] cis-5-methyl-trans-4-(2~propenyl)cyclohexanol was converted in quantitative yield to the title com-pound, an oil.
H.RMS (m/e) 480.3574 (M. , Calcd. for C32~803:
480.3591), 462, 395, 377, 287 and 91 (100%).
By means of thls procedure, CiS-3- [2-benzyloxy-4-(l,l-dimethylh~ptyl)phenyl]-cis-5-methyl-trans-4 (2-propenyl)cycloheptanol is converted to the corresponding 3-h~droxypropyl derivativeO
n 4 -1~8 ~
Cis-3-~4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-4-(3-hydroxypropyl)-cis-5-methylcyclohexanol Using the procedure o~ Example 6, 936 mg. (1.95 mmole) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-~hen~13-trans-4~3-hydroxypropyl~-c~s-S-meihylcycio-hexanol afforded 602 mg. ~79%) of the title compound.
~P 159-160C. (diisopropyl ether - ethyl acetate) IR (ECBr) 3533, 3367, 3211, 1617 and 1585 cm 1.
E{.RMS (m/e) 390.3100 (M~ , CaLcd. for C25H4203, 390.3123), 372, 304, 288, 287, 272, 257, 227, 219 and 187.
nal~sis:
. C c . r C25H42O3: C, 76.87; H, 10.84.
LS Found : C, 76.60; H, 10.66.
Similarly, cis-3-[2-benzyloxy-4-(1,1-dimethyl-hept~l)phenyl]-trans-4-(3-hydroxypropyl)-cis-5-methyl-cycloheptanol is debenzylated to the corresponding phenol.
n 4 --1~19`--Trans-3,4 t Trans-4,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl) phenyl]-4-~2-hydroxypropyl)-5-methylcyclohexanone _ ethylene ketal - - _ S To a 25C. mixture o~ 3 28 g. (10.3 mmole) of mercuric acetate in 50 ml. of 50~ aqueous tetrahydro-~-~an wa~ added 5~2 g. (10.3 m~ole) ~f trans-3,4,t~ans-4,5-3-[-2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~-5-methyl-4-(2-propenyl)cyclohexanone ethylene ketal in 25 ml~ tetrahydrofuran. Another 25 Ial. of water was added to aid solution and stirring. Additional l.S g~
(4.7 mmole~ portions of mercuric acetate were added after 2 hours and 24 hours~ The reaction was stirred a total of G4 hours at 25C. and then xeduced by addition of 20 ml. 3N sodium hydroxide and 20 ml. of 0.5M sodium borohydride in 3N sodium hydroxide. The reaction was stirred 30 minutes longer and then added to 250 ml.
etner - 300 ml. saturated sodium chloride. The ether extract was dried over magnesium sulfate and evapora~ed to an oil. The crude produc~ was puri~ied Yia column chromatography on 300 g. of silica gel eluted with 50%
ether-hexane to give 1~5 g. (30%) of the title compound as an oil.
HRM~ (m/e) 522.3712 (M+ , Calcd. for C34HSoO~l:
527.. 3~96), 431, 407, 372, 113 and 91 (100%).
PMR (CDC13) ~ 0.75 (m, terminal methyl~, 0.92 (d, J=6Hz, C-5 methyl), 1.24 (s, gem dimethyl), 3.35 (bm, carbinol and benzylic methines) 7 3-90 tbs, ethylene ketal), 5.03 (s, benzylic methylene) and 6.6-7.5 (m, Ar~I).
Trans-3,4-trans-4,5-3-[2-benzyloxy 4~(1,1-dimethyl-heptyl)phenyl]-4=(2-hydroxypropyl)-5~methylcyclohepta-none ethylene ~etal is also prepared via this procedure from the corr~sponding 4-(2-propenyl)cycloheptanone ethylene ketal~
t ~ 4~
r _ Trans-3,4,Tran~-~,5-3-[2-Benzyloxy-4-(1,1-dimethyl-heptyl)phenyll-5-methyl-4-(2-oxopropyl~cyclo-hexanone ethylene ketal To a 25C. mixture of 1.5 g. (2.87 mmole) of trans-3,~,trans-4,5-3-[2-~enæyl.oxy-4-(1,1-dimethylheptyl)-phenyl]-~-~2-nydIoxypTopyl3-~-met~ylc~clo~x~n~
ethylene ketal and 2.35 g. (28.7 mmole) of sodium acetat~
in 20 ml. of dichloromethane was added 1.93 g. (9 mmole) LO of pyridinium chlorochromate. The reaction mixture was stirred 3 hours at 25C~ and then added to 250 ml. lN
NaOH-250 ml. ethex. The organic extract was dried over magnesium sulfate and evaporated to gi~e a quantitative yi.eld oE the title compound as an oil.
PMR (CDC13) ~ 0.85 (m, methyls), 1-.23 (s, gem dimethyl), 1.80 (bs, CH3CO-), 2.23 (bs, -CH2CO-), 3~3 (m, benzylic methine), 3.93 - (s, ethylene ketal), 5.05 (s, ~enzylic methylene) and 6.7-7.6 (m, ~r~).
In like manner, oxidation of trans-3,4-trans-4,5-3-~2-ben2yloxy-4-~l,1-dimethylheptyl)phenyl]-4-(2-hydrox~propyl)cyclo}leptanone ethylene ketal af~ords .the corresponding 4-(2~oxopropyl)cycloheptanone ethylene ketal.
~ .
~ ~ 8 ~
--15 1_ -Trans-3,4-Trans-~,5-3-[2-Benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)-cyclohexa~one ethylen~ ketal S To a 15C. mixture of 5 . 74 mmole of triphenyl phos-phoniummethylide in 6 ml. of dimethyl sulfoxide was added æolu~ion of 1.5 g. ~2.~7 ~mole) of t~h~-3,~-trans~,3-3-[2-ben~yloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-t2-oxopropyL)cyclohexan~ne ethylene ketal in 6 ml. of tetrahydrofuran and the reaction stirred 1.5 hours at 15-25C. It was then added to 200 ml. saturated sodium chloride - 200 ml. ether. The ether extract was washed once with 200 ml. saturated sodium chloride, dried over magnesium sulfate and evaporated to give an oil. Puri fi~ation via column chromatography on 50 g. of silica gel eluted with 20~ ether-hexane gave 1.17 g. (79%~ of the title compound as an oil.
HRMS lm/e~ 518.3706 (M. , Calcd. for C35H50O3:
518.3747), 462, 427, 407, 372, 371, ~85 and 91 (100%).
PMR (CDC13~ ~ 1.25 (s, gem dimethyl~ 48 (bs, vinyl methyl), 3.3 (m, benzyllc methine), 3.89 (s, ethylene ketal), 4.40 (mt vinyl H~ t 5~02 ~s, benzylic methylene), 6.85 (m, ArH), 7.10 (d, J=8H~, ArH) and 7.4 (m, PhH).
Trans-3,4-trans-4,5-3-~2-bellzyloxy 4-(l,1-dimethyl-_ heptyl)phenyl~-5;methyl-4-(2-oxopropyl)cycloheptanone ethylene ~etal is converted in like manner to the corres-pondin~ 4~(2-methyl-2-propenyl)cycloheptanone ethylene ketal.
) 4 --15 2_ Trans-3,4-trans-4,5-3-[2-Benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)-_ _ cyclohexanone A mixture of 1.1 g. (2.12 mmole) of the ethylene Xetal of the title compound, 20 ml. tetrahydrouran and 20 ml. lN hydrochloric acid was heated at reflux for 5 hours and stirred at 25C. for 16 hours. The reaction was added to 250 ml. saturated sodium chloride - 250 ml~
ether. The ether extract was washed with 250 ml.
saturated sodium bicarbonate, dried o~er magnesium sulfate ~nd evaporated to give a quantitative yield of the ti~le compound as an oil.
H~MS (m/e) 474.3524 (M. , Calcd. for C33H46O2):
474.3486~, 418, 383, 327, 273 and gl (100~).
Deketalization of trans-3,4-trans-4,5-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methyl-4-(2-methyl-2-propenyl)cycloheptanone ethylene ketal is accomplished in like manner~
8~40~
Cis 3-[2-Benzyloxy~4-(1,1-dimethylheptyl)phenyl]~
cis-5-methyl-trans-4-(2-methyl-2-propenyl)-cyclohexanol and its axial Isomer Using the procedure of Ex~mple 13, 1.00 g. (2.12 mmole~ of trans-3,4-trans-4,5-3-Z2-benzyloxy-4-(1,1-~im~hylh~p~yl)~hn~1~-~is-5-me~h~l~ ranc-4~ .me~hyl-2-propenyl)cyclohexanon~ gave 248 mg. (25%) of the rans-3,ci~-4,trans-5 isomer of the title compound and 720 g. (71~) of the title compound as oils.
Trans-3, CiS-4, trans-5 Isomer:
~RMS (m/e) 476.3664 (M. , Calcd. for C33~48O2:
47~.3642), ~20, 335, 330, 329 (100~), 312, 311, and 283 Title Compound:
~RMS (m/e) 476.3646 (M+ , Calcd. for C33H~8O2:
476.3642~, 420, 330, 329 and 91 (100%).
Similarly trans-3,4-trans-4,5-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-methyl-trans-4~2-methyl-20 2-propen~l)cycloheptanone is transformed to Ci5-3- ~2-ben~yloxy 4-(1,1-dimethylheptyl)phenyl]-cis-5~methyl--trans-4-(2-methyl-2-propenyl)cycloheptanol and the corres-ponding axial derivative.
~ ~14l~
-154~
EXAMPLE_lO8 Cis-3-~2-Benzyloxy-4-(l,l-dimethylheptyl)phenyl3-trans-4-(3-hydroxy-2-methylpropyl)-cis-5-methylcyclohexanol Using the proc~dure of Example 5, 710 mg. (1.49 mmole) of CiS-3- [2-benzyloxy-4-tl,l-dimethylheptyl)-~hen~ ci~ met~yl-tr~ ;2-metnyl-~-propeny~-cyclohexanol (compound of Example 107~ gave 322 mg.
(44~) o~ diastereomer A and 356 mg. (48%) of dia-stereomer B of title compound as oils.
Dias~ereomer A:
HRMS (m/e) 494~3769 (M. , Calcd. for C33~5003o ~94.3747), 386, 301 and 31 (lO0~).
Diastereomer B~
lS ~RMS (m/e) 494.3790 (M. , Calcdu for C33H50O3:
494~3747) and 9l (lO0~.
In like manner, the remaining alkenyl dexivatives of Example 107 are hydrated to the corresponding alcohol~.
- 155 ~
EXhMPLE 1 O 9 Cis 3-[4 (1,1-dLm~thylheptyl)-2-hydroxyphenyl]-trans 4-(3-h~droxy-2-m~thylprop~ cis-5~methylcyclohexanol Diastereomex A
.
Using the procedure of Example 6, 320 mg. (0.648 ru~.~l~) o~ Ji~a.e~om~~ s~-{~-~e~ l~x~
dimethylheptyl)phenyll-trans-4-(3-hydroxy-2-methyl-~ropyl)-cis 5 methylcyclohexanol (product of Example 108) provided 221 mg. ~84~) of the title compound.
MP 139-141C. (diisopropyl ether-hexane) IR (C~C13) 3588, 3407, 1616 and 157~ cm 1, HRMS tm~e) 404.3247 (M. , Calcd. for C26H44O3:
404.3279), 386, 301, 233, 187, 161 and 147 (100%).
15 Analysis:
Anal. Calcd. fox C26H4~O3: C, 77-17; H~ 10-96-Found : C, 77.41; H, 10.77.
, Diaster omer B
Using the procedure of Example 6, 350 mg. (0.709 mmole) of diastereomer 8 of cis-3-[2-benzyloxy-~ (1,1-dime~h~lheptyl)phenyl]-trarls-4-(3-hydroxy-2-methyl-propyl~-cls~5-methylcyclohexanol (product of Example 108) ga~e 255 mg. (89~) of the title compound.
MP 118-120C. (diisopropyl e~her-hexane).
2S HRMS (m/e) 404.3237 (M~ , Calcd~ for C26H4403:
404.3279), 3~6~ 318, 301 (100~), 233, 187, 167 and 147.
t 18~ )4 EXAMPLE 109 (Conk.
, _ . .
Arlalys is:
Anal. Calcd. for C26H44O3: C, 77.17; H, 10.96~
Found : C, 77.40; ~, 10.76.
By means of this proce~ure, the remaining benzyl ethexs of Example 108 are converted to the corresponding phenols.
8 ~
.- 157 , 7-Oxabicyclo[4.1O0~-1-[2-penzyloxy-4-(1,1-dimethyl-_ heptyl)pheny~-3-heptanone ethylene ketal ~rO a 0C. solution of 5.0 g. (11.2 mmole) of 3~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-3-en-1-one ethylene ketal in 15 mlO of dichloromethane is added 1.26 g. (15 mmole3 of sodium bicarbonate and 2.58 g. (15 mmole) of m-chloroperbenzoic acid. The reaction is stirred overnight at 0C. and then filtered.
~he ~iltrate is diluted with 200 ml~ o~ ether and washed with two 100 ml. portions of saturated sodium bicarbonate.
The organic extract i5 dried over magnesium sulfate and evapo~a ted to yield ~he title compound .
~ :~g~o~
- 15~-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl~-4-hydroxycyclohexanone ethylene ketal Following the procedure of Example 6, 7-oxabi-cyclo[~i.l.O] 1-[2-benzyloxy 4-(1,1-dimethylheptyl)-phenyl3 3-heptanone ethylene ketai is nydrogenatea to give the title compound.
Deketalization acording to the procedure of Example ~ affords the corresponding ketone.
Following the procedures of Example 110, 3-[2-ben~yloxy-4~ dimethylheptyl)phenyl]cyclohept-3-en-1-one is converted to 3-[2-hydroxy-4-(1,1-dimethylheptyl)-phen~l~-4~hydroxycycloheptanone.
~ ~8~'~0~
EX~MPLE 112 Cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-hydroxycyclohexanol Sodium ~orohydride r~duction of 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-hydroxycyclohexanone according to the procedure of Example 2 affords the title compound.
Similarly, reduction of 3-[2-hydroxy-4-(1,1-dimethylheptyl~phenyl]~4-hydroxycycloheptanone afords the corresponding alcohol.
~ 18~4d~
PREPARATION A
6-(3-Butenyl)-3-ethoxy-2-cyclohexen-1-one A solution of 25 g. (0.178 mole) of 3-etho~y-2-cyclohexen-l-one in 25 ml. of tetrahydrofuran was added dropwise over a 30 minute period to a -78 C. solution of 0.196 mole of lithium diisopropylamide (from 27.4 ml., 0.196 mole, of diisopropylamine and 85 ml., 0.187 moles of 2.2M n-butyllithium in hexane) in 125 ml. of tetra-hydrofuran. The reaction was then stirred for 30 minutes a~d 65 ml. (0.374 mole) of hexamethylphosphoramide added followed by 38.9 ml. (0.383 mole) of 4-bromo-1-butene.
The reackion was then allowed to warm to room tPmperature, stirred for 1.5 hours and then quenched by addition of 5 mL. (0.277 mole) of water. Most of the solvent was removed on a rotovapor and the residue diluted with 1000 ml.
ice water and 500 ml. ether. The ether phase was separated, washed with two 300 ml. portions o water, dried over magnesium sulfate and evaporated on a rotovapor. Distil- -lation of the resulting crude oil gave 10.1 g. (29%) of ~he ~itle product~
b.p.: 83 C. (0.02 torr) PMR ~CDCl 1.34 (t, J=7Hz, methyl), 1~3 2.6 (m), 3.86 q~ J=7~z, methylene), 4.75-5.2 and 5.45-6.2 (m~
terminal olefin) and 5.26 (s, vinyl H).
In like manner, 6-t3-benzyloxypropyl)-3-ethoxy-2-cyclohexen-l-on was prepared from 12.9 g. (91.9 mmole) of 3-ethoxy~-oyclohexen-1-one and 28.0 g. ~101 mmole) of l-benzyloxy-3-iodopropane. Yield: 17.0 g. (67~).
Puriication was achieved via column chromatography on -161~
500 g. of 5~ ssdium bicarbonate silica gel eluted with 75% ether-hexane.
IR (CHC13) 1632 and 1600 cm 1.
MS (m/e) 288 (M ) PM~ ~CDC1 1.34 (t, J=7Hz, methyl~, 1.4-2.6 (m)~
3.50 (bt, J=6Hz, methylene), 3~85 (q, J=7Hz, methylene), ~.49 ~s~ benzylic methylene), 5~27 (s~ Yinyl Hl and 7.27 (s~ Ph.H)~
P~EPARATION B
.
4-(3 Butenyl)-2-~yclohexen-1-one . .
To a 0 C. slurry of 1.06 g. (26 mmoles) of lithium aluminum hydride in 75 ml. of ether was added a solution S of 10 g~ (51 mmoles) of 6-~3-butenyl)-3~ethoxy-2-cyclo-hexen-l-one in 25 ml, of ether. After stirring for one hour, the reaction was quenched by addition of lOO ml.
of 2~ hydrochloric acid. The quenched mixture was stirred for 30 minutes and then ex-tracted with 300 ml. of ether.
10 The ether extract was washed with 250 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated on a rotovapor. Distillation of the crude oil gave 5.98 g.
(78~) of the title product.
b.p.o 133-136 C. (22 torr) PMR ~cTDSl 1.3~2.7 (m), 4.9-5~4 tm, terminal olefin), 5.5 6.2 (m, terminal olefin), 5.02 (bd, J=~OHz, C-2 vi~yl ~) and 6.91 (bd, J=lOHz, C-3 vinyl H).
Similarly, 4-(3-benzyloxypropyl)-2-cyclohexen-1-one was prepared in 74~ (11.1 g.) yield from 17.0 g. (61.6 ~0 mmole) o~ 6-(3-benzyloxypropyl)-3~ethoxy-2-cyclohexen-1-one.
The product was an oil.
~R (CHC13) 1680 and 1459 cm 1.
PMR ~crDsl 1.2-2.8 ~m), 3.55 (bt, J=6Hz~ methylene), 4.50 ~s, benzylic methylene), 5.92 (dd, J=10 and 2Hz, Yinyl EI), 6.82 (bdt J=lOHz, vinyl H) and 7.33 (s, PhH).
~ .~ 8 ~ 4 PREPARATION C
2-~1,3-Dioxolan-2-yl)ethyltriphenylphosphonium bromide A sol-ltion of 25 g. (0.138 mmole) of 2 (2-bromoethyl~-1,3-dioxolane and 36.2 g. ~0.138 mmole) of triphenyl-phosphine in 30 ml. of toluene was heated at 100 C. for 18 hours. The reaction was cooled to yield two phases.
The toluene phase was decanted and the oil remaining crys-tallize~ at -78~ C. in ethyl acetate. Decantation of ~he ethyl acetate and warming of the crystals to room temperature gave an oil. The oil was dried under vacuum (0.05 torr) at 100 C. for 16 hours to yield lS g. (27%) o the title compound as a solid glass which was ground to a po~cler.
-16~ -PREPARATION D
-8-O~abicyclo[5.1.03octan-2-one To a 0 C. solution of 50.0 g. (0.454 mmole~ of cyclohept 2-en-1-one in 800 ml. o~ methanol was added 85 ml. of 30% hydrogen peroxide (0.75 mole~ followed by the dropwise addition o~ lS ml. of 6N sodium hydroxide (0.09 molel. The reaction was stirred for one hour and then added to il00 ml. ethex-500 ml. petroleum ether.
The ether extract was removed and the aqueous methanol phase extracted wlth ~our 500 ml. portions of petroleum ether and three 300 ml. portions of dichloromethane.
The combined organic extracts were washed with three 800 ml. por~ions of saturated sodium chloride, dried over magnesium ~ulfate and evaporated under reduced lS pressure to an oil (53 g.). The crude oil was purified via vacuum distillation to yield 45.9 g. (80%) of the title compound as an oil. Caution: several ~orceful detonations have occurred during distillation of the crude productO (In general, however, the crude product is pure enough for further synthetic manipulations and distillation can be avoided.) h.p.: 89~90 C. (14 torr~
IR (C~C13) 1695 and 1600 cm 1~ .
MS (m,~e~ 126 (M ), 99, 98, 97 and 84.
~S PMR ~CDCl 0.7-1.5 (m), 1.5-3~0 (m) and 3.48 (d, J=3EIz, C-LH~. 3 ~ :~ 8 ~
_165_ .
PREPARATION E
_Hydroxycycloheptanone To a 25 C. solution of 45.9 g.. (0.364 mole) of 8-oxabicycl.o[5.1~0]octan-2-one in 950 ml. of 10~
a~ueous tetrahydrofuran was added 39.7 g. (1.47 mmoles) of aluminum amalgam~ (The aluminum amalgam was prepared by 15-30 second successive washing of small pieces o~
aluminum foil with 2N sodium hydroxide, distilled water, O.5% mercuric chloride, distilled water, 2N sodium h~droxide, distilled water, 0.5% mercuric chloride, distilled water, ethanol and ether.) The mixture was stirred ~or 2 hours, then filtered through diatomaceous earth. The filtrate was evaporated on a rotovapor, the residue saturated with solid sodium chloride and extracted lS with three 5Q0 ml. portions of ether. The ether e~tract was dried over magnesium sulfate and evaporated to yield 45 g. (97~) o~ the title compound as an oil.
IR (CHC13) 3390, 1695 and 1610 cm 1 MS (mfe) 128 (M ), 110, 100 and 85.
PMR ~cMcl 1.80 (m), 2.42 (m, C-7 methylene)/ 2.89 (d, ~=6Hz, C-2 methylene), 3.40 (bs, OH) and 4.0~ (m, C~3 methine).
~ ~#~0~
_166 _ PREPARATION F
Cycloheptan-1,3-dione To a 10 - 20 C. solution of 20 g. (0.156 mole~
of 3-hydroxycyclohep`~tanone in 700 ml. of acetone was slowly added 5~.9 ml. of 2.67 M Jone's reagent (0.146 mole). The mixture was stirred 15 minutes and then ~uenched ~y addition of 12 ml. of isopropanol. The reaction was ~iltered through diatomaceous earth and the filtrate concentrated on a rotovapor to about 100 ml.
$he residue was diluted with 300 ml. of saturated sodium chloride and then extracted with six 250 ml. portions of ether. The combined organic extract was washed with two 100 ml. portions of saturated sodium bicarbonate, dxied over magnesium sulfate and evaporated under reduced pressure ~aspirator) to yield an oil. Distillation of the crude oil gave 11.5 g. (58~) of the title compound as an oil.
b~p.: 117-~21 C. (14 torr) IR (C~C133 3S09 (weaX~, 1733, 1704 and 1621 cm lu MS (m~e) 126 (M ), 98~ 83 and 70.
PMR ~CDC13 2.0 (m, C-S,~ methylenesj, 2.58 (m, C-4,7 methylene) a~d 3.60 (s, C-2 methylene).
, , ., PREPARATION G
3-Ethoxycyclohept-2-en-1-one _ .
A solution of 220~ g. (0.177 mole) of cycloheptan-1,3-dione and 600 mg. (3.16 mmoles) of p-toluenesulfonic acid monohydrate in 86 ml. o ethanol and 250 ml. of toluene was heated at re~lux for 18 hours. A soxhlet extractor filled with molecl~lar sieves (3A) was used to remove water from the reaction. The reaction was cooled, added to 800 ml. saturated sodium chloride and e~tracted with four 800 ml. portions o~ ether. The combined organic extract was dried over magnesium sulfate and e~aporated to an oil. Distillation of the crude oil gave 25.3 g. (93~) of the title compound as an oil.
b.p.: 74-78 C. (0.10~0.15 torr) IR (Neat) 1645 and 1613 cm 1, MS (m/e) 154 (M ), 135, 109, 98 and 97.
PMR ~cDMcl 1.34 (t, J-7Hæ, methyl), 1.8 (m, C-5,6 methylenes), 2.6 (m, C-4,7 methylene), 3.80 (q, J=7Hz, ether methylene) and 5.37 (s, olefinic H).
PREPARATION H
3-Ethoxy-7-(2-propenyl)cyclohept-~-en-1-one Following Preparation A, 15 g. (97.4 mmole) of 3-ethoxycyclohept-2-en-1-onP and 23.5 g. (0.195 mole) o~ allyl bromide gave 11.4 g. (60%) of the title compound as an oilO
.p.: 80-87 C. (0.05-0.1 torr) IR (Neat) 1650 and 1608 cm 1.
~IS (m/e) 194 (M ) P~ ~CDCl 1.38 (t, J=7Hz, methyl), 1.4-3.1 (m), 3.87 (q, J=7Hz, ether methylene), 4.9-5.3 and 5.4-6.3 (m, olefinic) and 5.42 (s, C-2 vinyl H)~
,~ ~,8~,4~r,~
-1~8~
PRE~ARATION I
4-(2~PropenylJcyclohept-2-en-1-one Following Preparation B, 12.0 g. (61.8 mmole) of 3-e~hoxy~-7 (2-propenyl)cyclohept~2-en-1-one gave 3.0 gO
(33~) of the title compound as an oil.
b.p.: 71-72 C. (0.1 torr) IR ~eat~ 1678 (broad~ cm 1 MS (m/e) 150 (M ) PMR ~CDCl 1.2-3.0 (m), 4.8-6.1 (m, terminal olefin), 5.96 (dd, J=12 and 2Hz, C~2H) and 6.42 (dd, J=12 and 3Hz, C~3~)-PREPARATION J
(R)-l~Bromo-2~benzyloxy-4-tl-methyl-4-phenyl-_ bu~oxy)benzene A mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophe.nol, 20.0 g. (82.6 mmole) of (S)-l-methyl-4-phenylbutyl methane sulfonate and 25.2 g. (200 mmole) of potassijm carbonate in 100 ml. dlmethyl~ormamide was heated at 85 C. for 13.5 hours. The reaction was cooled and ~dded to 500 ml. water-500 ml. ether~ The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil.
The crude oil was pu~ified via column chromatography on 750 g. of silica gel eluted with 10~ ether-hexane to ~5 yield ~3~9 g. (72%) of the title compound as an oil~
~]25 = -11.39 tC = 1.137, CH3Cl) IR (CHC13) 1574 cm 1 E~MS tm/e) 426.1011 (M , calc'd. for C24~2502Br:
426.1012) t 424, 280, 278, 104 and 91.
PMR (CDC13)~ 1.22 (d, J=6Hz, methyl), 1.4-2.0 (m), Z.60 (m, benzylic methylene), 4.24 (m, methine), 5.07 (s, benzyLic methylene), 6.30 (d, J=2Hz and 8Hz, ArH), 6.46 (d, J=2Hz, ArH), 7.17 (s, PhH) and 7.35 (m, PhH).
I~#~33' PREPARATION K
-l-Benzyloxy-3 lodopropane To a solution of 83.3 g. (0.318 mole) triphenyl-phosphine in 200 ml. benzene was added, in four portions, 80 g. (0.318 mole) of iodine. The resultant mixture was stirred 3 hours and th~n 50 ml. (0.618 mole) of pyridine was added followed by the slow addition of 32 g. (0.192 mole) of 3~benzyloxypropanol in 250 ml. of benzene.
The xeaction was stirred 15 hours longer and then diluted with 40 ml~ of methanol. The mixture was filtered through diatomaceous earth and the filtrate evaporated to an oil.
Distillation of the crude oil yielded 28 g. (53~) of the title compound as an oil.
b.p.: 94-97 C. (0.45 torr) PMR (CDC13)~ 2.00 (quintet, J=6Hz, methylene), 3.20 (~, J=6Hz, methylene~, 3.43 (tr J=6Hz, methylene), 4.42 (s, benzylic methylene) and 7.20 (s, PhH).
.
.-- ~
I :~s~n~
-lf o PREPARATION L
_.
(R)-l-Bromo-2-benzyloxy-4-(l~methyl-4-phenylbutoxy)b nzene A mixture o~ 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophenol, 20.0 g. (82.6 mmole) of (S)-l-methyl-4-phenylbutyLme~hane sulfonate and 25.2 g. (200 mmole) of potassium caxbonate in 100 ml. dimethylformamide was heated at 85 C. for 13.5 hours. The re~ction wa~
cooled and ~dded to 500 mlO water-500 ml. ether. The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chroma-tography Oll 750 g. of silica gel eluted with 10~ ether-hexane ~o yield 23.9 g. (72%) of the title compound as lS an oil.
[]25 = ~11.39 (C = 1.137, CH3Cl) IR (CHC13) 1574 cm 1.
HRMS (m~e) 426.1011 (M~, Calc'd for C24H25V2Br, 426.1012), 424, 280~ 278, 104 and 91.
CDC13 1.22 (d, J=6Hz, methyl), 1.4-2.0 (m) 2.60 ~m, benzylic methylene), 4.24 (m, methine), 5.07 ts, benzylic methylene), 6.30 (d~ J=2Hz and 8Hz, ArH), 6.~6 (d, J=2Hz, ArH), 7.17 (S, PhH) and 7.35 (m, PhH)_ 1, ~ 8 ~
--171 _ PREPARATION M
~-(3-Hydroxyphenyl)-2-methylpropanal . _ .
A mixture of 38.9 g. ~0.153 mole) of 2-(3-benzyloxy-phenyl)-2-me-thylpropar.al, 20 g. 5~ Pd/C/50~ water, 1.0 S sodium bicarbonate and 150 ml. ethanol was shaken over-ni~ht under 55 psi of hydrogen. The reaction was filtere~
through diatomaoeous earth, the filt~r cake washed with ethanol and the comblned filtrate evaporated. The residue was reduced as abQve for another 8 hours. Another 10 g.
portion of catalyst was added and the reaction continued overnight. The reaction was worked-up as above and the residue purified via column chromatography on 500 y. of silica gel eluted with 25~ ether-hexane to yield 14 y. ~56~) of the title compound as an oil.
L5 PMR (CDC13~ 42 (s, gem dLmethyl), 6.36 (bs, OH), 6.7-6.9 ~m, ArH), 7.05-7.2 (m, ArH) and 9.62 (s, CHO).
" .
~ ~q ~
PREPARATION ~
2-[3-(Tetrahydropyranyl-2-oxy)phenyl]-2-methylpropanal To a 0C. solution of 11.3 g. (0.0688 mole~ of 2-(3-hydro~yphenyl)-2~me-thylpropanal and 11.1 mlO (0~122 S mole) of dihydropyran in 113 ml. dichloromethane was added several cxyst ls of p-toluenesulfonic acid mono-nydrate. ~Fne reaction was stirred one hour at 0C.
and then added to 60 ml7 saturated sodium bicarbonate -460 ml. ether. The ether extract was washed once with ].00 ml. saturated sodium chlorids, dried over magnesium sulfate and evaporated to yield 15.3 g. (89%) of the title compound as an oil.
IR (CHCl3) 1727, 1603 and 1582 cm 1.
PMR (CDC13) ~ 1.48 (s, gem dimethyl), 1.5-2.1 (m~, 3.4-4.2 (m), 5.37 (m, methine), 6.7-7.4 (m, ArH) and 9.53 (s, C~O).
8~4 PREPARATION o l,l-DLmethyl-l [3-(tetrahydropyranyl-2-oxy)-phenyl]-cis-2-heptene To a 15C. solution of 75.5 mmole of dimsyl sodium (from sodium hydride and dimethyl sulfoxide) in 3a ~1~ dime~hyl sulo~ide was added portionwise7 31.2 g. (75.5 mmole) of n-pentyltriphenylphosphonium bromide~ The resultant slurry was stirred 30 minu~es and ~he 15.3 g. (61.6 mmole) of 2-[3-(tetrahydro-pyranyL-2-oxy)phenyl]-2-methylpropanal was added over lS minutes. The reaction mixture was stirred 50 minutes at 15C. and then added to 800 ml. ice -800 ml. ether. The a~ueous phase was extracted twice with 400 ml~ of ether. The combined ether extract was lS wa~hed once with 250 ml.,water and once with 250 mlO
saturated sodium chloride, dried over maynesium sul-fate and evaporated to yield an oil. Triphenylphos-phine oxide was removed by crystallization from pentane. The remaining oily residue was puri~ied via column chromatography on 1 kg. of silica gel eluted with 0.75~ ether-h~xane o yield 17.7 g. (95%) o~ the title compound as an oil.
IR (CMC13) 1603 and 1581 cm 1, P~R ~CDC13) ~ 0.76 (ml terminal CH3), 1.20 (st gem 2S dimethyl), 3.3-4.1 (m), 4,9_S~a (m, 2H), 5.56 (d, J=12~z) and 6.6-7.3 (m, ArH).
~ ~ ~s ~
--17~1--P REPARAT I ON P
Trans~3 methyl-4-(2-propenyl)cyclohexanone ... .. ..~
To a 0C. solution of 0.282 mole of dimethyl copper lithium in 200 ml. of tetrahydrofuran was S slowly added a solution of 25.6 g. (0.188 mole) of 4-~2 propenyl)cyciohex-2-en-~one in ~0 ml. ~f tetr~
hydrofuran. The reaction was stirred 15 minutes and then quenched by addition to a 0C. saturated solution (500 ml.) of ammonium chloride. The quenched reaction was extracted with 500 ml. ether. The ether extract was w~shed with 500 ml. saturated ammonium chloride, dried over magn sium sulfate and evaporated to an oil which was purified via distillation to yield 15.5 g.
(5$%) of the title compound.
BP 110-113C. (15 torx) ~R (CH~13) 1710 and 1640 cm 1.
MS (m/e~ 152 (M ), 136, 110.
~nalysis:
Calcd. for CloH16O: C, 78.8g; H, 10.59.
Found : C, 78.76; H, 10.24.
P~R (CDC13) ~ 1.05 (d, J=6Hz, methyl), 1.0-3.0 (m), 4,8-5.3 (m, vinyl H) and 5.4-6.1 (m, vinyl H).
SLmiliarly, trans~3-methyl-4-(2-propenyl)cyclo-~heptanone is produced from 4-(2-propenyl)cyclohept-2-25 e~ one.
~ ~8~4(~4 -175_ PREPARATION Q
~-Methyl-4 (2-propenyl)-2-phenylsulenyl-cyclohexanone To a 0C. mixture of 16.9 g. (0.109 mole) of methyl benzenesulfinate and 8~68 g. (0.217 mole~ of potassium hydride in 100 ml. of dimethoxyethane was - slowly added a solution of 15.0 g. (0.0987 mole) of trans-3-methyl-4-(2-propenyl)cyclohexanone in 50 ml.
of dimethoxyethane~ The reaction was stirred 30 minutes longer at 0C. and then cautiously added to 500 ml. of ice-saturated sodium chloride and 45 ml. 6N
hydrochloric acid. The quenched reaction micture was extracted once with 300 ml. ether and once with 200 ml. dichloromethane. The organic extract was lS driecl over magnesium sulfate and evaporated to give a quantitative yield o~ the title compound as a semisolid mixture of axial and equatorial sulfenates. Crystal-lization from ether yields 7.8 g. of pure axial sul-~ena~e.
A:cial Sulfenate:
PMR (CDCl3) ~ 1.05 (d, J=5Hz, methyl~, 1.0-1`
2.7 (m), 3.39 (dd, J=ll and 6Hz, CHS), 4.7-5.2 (m, vinyl H), 5.3~6.1 tm, vinyl H) and 7.4 (m, PhH).
~5 In like manner, 3-methyl-4-(2-propenyl)cyclohept-2-en-1-one is converted to 5-methyl-4~ propenyl)-2-phenylsulfenylcycloheptanone.
- \
PREPARATION R
Trans-5-methyl-4-(2-propenyl)cyclohex-2-en-l-one ~ mi~ture of 96.7 mmole of 5-methyl-4-(2-propenyl)-2-phenylsulfenylcyclohexanone and lO g, (lOO mmole) of S calcium carbonate in 300 ml. of toluene was heated at C for ~0 mi n~es. The re~ction ~ c~o~
magnesium sulfate added and filtered. The filtrate was evaporated and the residue purified via column chromatography on 300 g. of silica gel eluted with 20%
ether-hexane and then distillation to yield 7.61 g.
~52~) of the title compound.
BP 50~C. (0.03 torr).
PMR (CDCl3) ~ l.ll (d, J=6Hz, CH3), 1.3-2.g (m) 4.8-5.3 (m, vinyl H~, 5.3-6.2 (m, vinyl H), 5.95 (bd, J=lOH~, C-2 H) and 6.80 (bd, J=lOH2, C-3 H).
By means of this procedure, 5-methyl-4-(2-propenyl)-2-phenylsulfenylcycloheptanone is converted to trans S-methyl-4-(2-propenyl)cyclohept-2-en-l-one.
PR~ARATION S
3-~2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cyclohex-3-en-l~one ethylene ketal A solution of 500 mg. of 3-t2~benzYloxy-4-(1~1-dime~hylheptyl)phenyl]cyclohex~2-en-1-one, 7.8 g. o~
ethylene glycol, 375 mg. of hydroquinone and 50 mg. of ~-toluenesulfonic acid monohydrate in 50 ml. of benzene i5 hea-ted at reflux for 12 hours using a Dean Star.~ condensor filled with 3~ molecular sieves. The reaction is cooled, added to 500 ml. saturated sodium bicarbonate and the quenched mixture extracted wi-th three 150 ml. portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid is puri~ied via column chromatography on 50 g. of silica lS gel eluted with 50% ether-petroleum ether to yield the title product.
Similar1y, 3-[2-benzyloxy-4-tl,l-dimethylheptyl)-phenyl]cyclohept-3-ex~ one ethylene ketal is prepared Prom 3-~2-benzyloxy~4-(1,1-dimethylheptyl)phenyl~-cyclohept-2-en-1-one.
PREPARATION T
-3-[2-~enzyloxy-4-(l,l-dimethylheptyl)phenyl]-cYclohex-2~enone A solution of 3.89 g. (l0 mmoles) of 2-(3-benzyl-oxy 4-bromophenyl)-2-methyloctane in l0 ml. of tetra-hydro~uran was slowly added to 360 m~. 114.4 mmoles~
o~ 70-80 m~sh magnesium metal. The resulting mixtuxe was refluxed for 30 minutes and then cooled to 0C.
To this solution was slowly added a solution of l.~0 g.
L~ (l0 mmoles) of 3-ethoxy-2-cyclohexen-l-one in 3 ml. of tetrahydrouran. The reaction mixture was stirred for 30 minutes at 0C. and then quenched by the addition o~ 20 ml. of lN sulfuric acid and heating on the steam bath ~or 30 minutes. It was then cooled and added to L5 200 ml, of ether - 200 ml. of water. The organic extrac~ was washed successively with 200 ml. of satu-rated sodium b1carbonate and 200 ml. o~ saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified via column chrom~tography on 170 g. of silica gel eluted with l:l ether:pentane to yield 2.5 g. (54~) of the title compound as an oil.
IR (CHCl3) 1667, 1610 and l558 cm l.
MS (m/e) 404 (M ), 3l9, 313 and 9l.
In like manner, 3-~2-benzyloxy-4-(l,l-dimethyl-heptyl)phenyl]cyclohepten-2-enone is prepared ~rom 3-ethoxy-2 cyclohepten-l-one.
~ ~8~L~()4 _179 _ PREPARATION U
6-[2-Benzyloxy 4-(l,l-dimethylheptyl~phenyl]-cYclohept-3 en-l-one To a 0C. slurry of 2.L9 g~ ~0.055 mole) of potassium hydride in 20 ml. of dimethoxyethane is ad~e~ 4.3~ 0.0~ -mule~ o~ ~ei*yi pnenylsulrinate.
To the resultant mixture is added, dropwise over a 30 minute period, a solution of 9~82 g. ~0.024 mole) of 3-~2-benzyloxy-~-(1,1-dimethylheptyl)phenyl]cyclo-heptanone in 20 ml. of dimethoxyethane. The reactionis stirred one hour at 0C. and then quenched by dropwise addition of l ml. of water. The quenched reaction mixture is added to 15 ml. ether ~- 15 ml.
dichloromethane -- 12.5 ml. 6N HCl-40 ml. satura~ed sodium chloride. The aqueous phase is extracted with another lS ml. portion of dichloromethane. The com-bined organic extract is dried over magnesium sulfate and evaporated to a semisolid. It is used as is in the next step.
The crude product thus obtained is mixed with 2.68 ~. (0.026~ mole) of calcium carbonate in lO0 ml.
of toluene and heated at 110C. for 30 minutesO The reaction mixture is cooled, filtered through magnesium sulfate and the filtrate evaporated on a rotovapor to yield an oil which was purified via column chroma-tography on 500 g. of silica gel eluted with 39%
ether-hexane to yield the title compound.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for making a compound having formula (II) (II) wherein R1 is hydrogen, alkanoyl having from one to five carbon atoms, or a hydroxy-protecting group selected from the group consisting of a lower alkyl, tetrahydropyranyl, benzyl and a substituted benzyl having as the substituent alkyl having from one to four carbon atoms, halo or alkoxy having from one to four carbon atoms;
s is an integer of 1 or 2;
W is hydrogen, pyridyl or - Wl wherein Wl is hydrogen, chloro or fluoro, provided that when W is hydrogen, Z is (a) alkylene having from five to thirteen carbon atoms; or (b) -(alk1)m-0-(alk2)n-wherein each of (alk1) and (alk2) is alkylene having from one to thirteen carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk1) plus (alk2) is not less than five or greater than thirteen; and at least one of m and n is 1; or (c) -Z-W is 1,1-dimethyl-2-heptenyl;
when W is other than hydrogen, Z is (a) alkylene having from three to eight carbon atoms; or (b) -(alk1)m-O-(alk2)n-wherein each of (alk1) and (alk2) is alkylene having from one to eight carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk1) plus (alk2) is not less than three or greater than eight; and at least one of m and n is 1;
Y is -CH(R2")CH(R2)- or -CH(R3)CH2- wherein R2" is hydrogen or methyl, R2 is a 4-position substituent and is oxoalkyl with up to six carbon atoms and R3 is a 5-position substituent and oxoalkyl with up to three carbon atoms; which process comprises (A) oxidizing a compound of formula (II"), or a ketal thereof, (II") wherein s, R1, Z and W are as defined above; and Y" is -CH(R2")CH?R20)- or -CH(R30)CH2- wherein R2" is as defined above, R20 is a 4-position substituent and is alkenyl with up to six carbon atoms and R30 is a 5-position substituent and is alkenyl with up to three carbon atoms, or (B) oxidizing a compound of formula (II"'), or a ketal thereof, (II"') wherein s, R1, Z and W are as defined above; and Y"' is -CH(R2")CH(R200)- or -CH(R300)CH2- wherein R2" is as defined above, R200 is a 4-position substituent and is hydroxy-alkyl with up to six carbon atoms,and R300 is a 5-position substituent and is hydroxy-alkyl with up to three carbon atoms, (C) reacting a Grignard reagent derived from a compound of the formula wherein Z and W are as defined above, R1' is the hydroxy protecting group defined above, with 4-(acetal or ketal substituted alkyl)-2-cycloalken -1-one of the formula wherein R2" and s are as defined above, R6 is acetal or ketal substituted alkyl, corresponding to the radical R2 defined above, (D) subjecting 4- or 5-oxoalkyl in a 4- or 5- oxoalkyl-3-phenyl-cycloalkan-1-one C-1 ketal of the formula wherein Z, W and s are as defined above, R1' is the hydroxy protecting group defined above, V is -CH(R2")CH(R4)- or -CH(R5)CH2- wherein R2" is hydrogen or methyl, R4 is a 4-position substituent and is oxoalkyl with less carbon atoms than the desired radical R2 and R5 is a 5-position substituent and is oxoalkyl with less carbon atoms than the desired radical R3, to the Wittig reaction, followed by reduction of thus prepared 4- or 5-w-oxoalkenyl compound, so as to prepare a compound of formula (II) wherein R2 or R3 is .omega.-oxoalkyl, (E) reducing cyano group in a compound of the formula wherein R1. s, Z and W are as defined above, or a ketal thereof, to the formyl group, and (F) when required converting the ketal to the corresponding ketone and/or removing the hydroxy protecting group, and/or acylating the hydroxy group.
s is an integer of 1 or 2;
W is hydrogen, pyridyl or - Wl wherein Wl is hydrogen, chloro or fluoro, provided that when W is hydrogen, Z is (a) alkylene having from five to thirteen carbon atoms; or (b) -(alk1)m-0-(alk2)n-wherein each of (alk1) and (alk2) is alkylene having from one to thirteen carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk1) plus (alk2) is not less than five or greater than thirteen; and at least one of m and n is 1; or (c) -Z-W is 1,1-dimethyl-2-heptenyl;
when W is other than hydrogen, Z is (a) alkylene having from three to eight carbon atoms; or (b) -(alk1)m-O-(alk2)n-wherein each of (alk1) and (alk2) is alkylene having from one to eight carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk1) plus (alk2) is not less than three or greater than eight; and at least one of m and n is 1;
Y is -CH(R2")CH(R2)- or -CH(R3)CH2- wherein R2" is hydrogen or methyl, R2 is a 4-position substituent and is oxoalkyl with up to six carbon atoms and R3 is a 5-position substituent and oxoalkyl with up to three carbon atoms; which process comprises (A) oxidizing a compound of formula (II"), or a ketal thereof, (II") wherein s, R1, Z and W are as defined above; and Y" is -CH(R2")CH?R20)- or -CH(R30)CH2- wherein R2" is as defined above, R20 is a 4-position substituent and is alkenyl with up to six carbon atoms and R30 is a 5-position substituent and is alkenyl with up to three carbon atoms, or (B) oxidizing a compound of formula (II"'), or a ketal thereof, (II"') wherein s, R1, Z and W are as defined above; and Y"' is -CH(R2")CH(R200)- or -CH(R300)CH2- wherein R2" is as defined above, R200 is a 4-position substituent and is hydroxy-alkyl with up to six carbon atoms,and R300 is a 5-position substituent and is hydroxy-alkyl with up to three carbon atoms, (C) reacting a Grignard reagent derived from a compound of the formula wherein Z and W are as defined above, R1' is the hydroxy protecting group defined above, with 4-(acetal or ketal substituted alkyl)-2-cycloalken -1-one of the formula wherein R2" and s are as defined above, R6 is acetal or ketal substituted alkyl, corresponding to the radical R2 defined above, (D) subjecting 4- or 5-oxoalkyl in a 4- or 5- oxoalkyl-3-phenyl-cycloalkan-1-one C-1 ketal of the formula wherein Z, W and s are as defined above, R1' is the hydroxy protecting group defined above, V is -CH(R2")CH(R4)- or -CH(R5)CH2- wherein R2" is hydrogen or methyl, R4 is a 4-position substituent and is oxoalkyl with less carbon atoms than the desired radical R2 and R5 is a 5-position substituent and is oxoalkyl with less carbon atoms than the desired radical R3, to the Wittig reaction, followed by reduction of thus prepared 4- or 5-w-oxoalkenyl compound, so as to prepare a compound of formula (II) wherein R2 or R3 is .omega.-oxoalkyl, (E) reducing cyano group in a compound of the formula wherein R1. s, Z and W are as defined above, or a ketal thereof, to the formyl group, and (F) when required converting the ketal to the corresponding ketone and/or removing the hydroxy protecting group, and/or acylating the hydroxy group.
2. A compound having formula (II) as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3, A process according to claim 1, wherein in formula (II"), (II"') and (II), s is 1, W-Z- is C7-11 alkyl; alkyl; pyridyl-C4-7 alkyl;
wherein m is O or 1, n is 1 and each of (alk1) and (alk2) is C1-7 alkylene with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not less than four or greater than seven; or H-(alk2)n-0-(alk1)m- wherein m is O or 1, n is 1 and each of(alk1) and (alk2) is C1-11 alkylene with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not less than four or greater than eleven.
wherein m is O or 1, n is 1 and each of (alk1) and (alk2) is C1-7 alkylene with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not less than four or greater than seven; or H-(alk2)n-0-(alk1)m- wherein m is O or 1, n is 1 and each of(alk1) and (alk2) is C1-11 alkylene with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not less than four or greater than eleven.
4. A process according to claim 1, wherein in formulae (II"), (II"') and (II), s is 1, R2" is hydrogen and W-Z- is H(CH2)6(CH3)2C-, C4-7 alkyl, C7-9 alkyl-O- or C4-5 alkyl-O-.
5. A process according to claim 4, wherein in formulae (II"), (II"') and (II), W-Z is H(CH2)6 (CH3)2C-.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000444792A CA1181404A (en) | 1980-09-19 | 1984-01-05 | 4-or 5-oxoalkyl-3-phenyl-cycloalkan-1-one derivatives |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18879580A | 1980-09-19 | 1980-09-19 | |
| US188,795 | 1980-09-19 | ||
| CA000386091A CA1170656A (en) | 1980-09-19 | 1981-09-17 | Pharmacologically active 2-hydroxy-4- (substituted)phenyl cycloalkanes, derivatives thereof and intermediates therefor |
| CA000444792A CA1181404A (en) | 1980-09-19 | 1984-01-05 | 4-or 5-oxoalkyl-3-phenyl-cycloalkan-1-one derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000386091A Division CA1170656A (en) | 1980-09-19 | 1981-09-17 | Pharmacologically active 2-hydroxy-4- (substituted)phenyl cycloalkanes, derivatives thereof and intermediates therefor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1181404A true CA1181404A (en) | 1985-01-22 |
Family
ID=27167138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000444792A Expired CA1181404A (en) | 1980-09-19 | 1984-01-05 | 4-or 5-oxoalkyl-3-phenyl-cycloalkan-1-one derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1181404A (en) |
-
1984
- 1984-01-05 CA CA000444792A patent/CA1181404A/en not_active Expired
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